N-(amidinophenyl) cyclourea analogs as factor XA inhibitors

ABSTRACT

The present application describes N-(amidinophenyl)cyclourea analogs of formula I: which are useful as inhibitors of factor Xa.

This application claims benefit of provisional application 60/015684 filed Apr. 17, 1996.

FIELD OF THE INVENTION

This invention relates generally to N-(amidinophenyl)cyclourea analogs which are inhibitors of factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

Bovy et al, U.S. Pat. No. 5,430,043 describe phenyl amidines of the formula: ##STR2## which are reported to be platelet aggregation inhibitors. However, no mention is made of inhibiting Factor Xa.

Himmelsbach et al, CA 2,105,934, address cyclic ureas of the formula: ##STR3## wherein, among the multitude of choices, X may be a carbonyl, Y may be an C₂₋₄ alkylene, R_(a) may be A--B--C-- and R_(b) may be --D--E--F. Group F is selected from --CO₂ R, phosphono, tetrazolyl, and R₈ CO--O--CHR₉ --O--CO--. The compounds described by the above formula are alleged to have aggregation inhibiting and/or fibrinogen binding properties. Factor Xa inhibiting is not discussed.

Lam et al, WO 94/19329, report cyclic carbonyls which may be cyclic ureas of the formula: ##STR4## wherein at least one of R⁴, R^(4a), R⁷, and R^(7a) is other than hydrogen. Compounds of this sort are said to be useful as HIV protease inhibitors. N-(Amidinophenyl)cycloureas are not suggested as factor Xa inhibitors.

Currie et al, WO 96/36639, set forth amidine derivatives of the formula: ##STR5## wherein A may be a 6-membered cyclic urea, which may be useful as anti-platelet aggregation inhibitors. However, Y is nitrate, nitrite, or a nitric oxide donating group. The present compounds, in contrast, do not contain the nitric oxide donating groups of WO 96/36639.

Klinger et al, WO 94/21607, illustrate heterocyclic compounds of the formula: ##STR6## wherein, upon judicious selection of variables, Z¹ may be a carbonyl, A may be NR¹, R¹ may be an amidino-substituted phenyl, and B and Z² may each be CH₂. However, the present compounds do not include the right-side chain shown above.

Mohan et al, WO 96/38421, describe N,N-di(arylmethyl)cyclic urea derivatives of the formula: ##STR7## wherein R⁷ and R⁸ may combine to form a benzene ring and the double bond shown may be absent, which may be useful as Factor Xa inhibitors. These compounds are preferably bis-amidino substituted. However, the presently claimed compounds are neither bis-benzyl nor bis-amidino substituted.

Chakravarty et al, WO 95/03044, discuss benzimidazoles substituted with phenoxyphenylacetic acid dervatives of the formula: ##STR8## wherein R¹² may be a substituted aryl group. But, this reference does not consider amidino-phenyl groups. Furthermore, the present compounds do not contain the above variable Z, which is defined as a carbonyl, sulfonyl, or phosphoryl group.

Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient that inactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel N-(amidinophenyl)cyclourea factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I): ##STR9## or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R¹, R², m and n are defined below, are effective factor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

1! Thus, in a first embodiment, the present invention provides novel compounds of formula I: ##STR10## or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein;

one of D and D' is selected from CN, C(═NR¹¹)NR¹² R¹³, NHC(═NR¹¹)NR¹² R¹³, NR¹² CH(═NR¹¹), C(O)NR¹² R¹³, and (CH₂)_(t) NR¹² R¹³ and the other is H;

R¹ is selected from H, (CH₂)_(r) OR³, halo, C₁₋₄ alkyl, (CH₂)_(r) NR⁴ R^(4'), (CH₂)_(r) CO₂ H, (CH₂)_(r) C(═O)R⁴, (CH₂)_(r) NR⁴ C(═O)R⁴, (CH₂)_(r) SO₂ R⁵, and (CH₂)_(r) NR⁴ SO₂ R⁵ ;

R² is selected from H, ═O, C₁₋₄ alkyl substituted with 0, 1, or 2 R⁷, C₂₋₆ alkenyl substituted with 0, 1, or 2 R⁷, (CH₂)_(r) OR³, (CH₂)_(r) C(O)R⁴, (CH₂)_(r) OC(O)R⁴, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) NR³ C(O)R⁴, (CH₂)_(r) SO₂ R⁵, (CH₂)_(r) NR³ SO₂ R⁵, C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R^(2a) is absent;

alternatively, R² and R^(2a) may be present on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R¹⁰ or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 R^(10a) ;

R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, benzyl and phenyl;

R³ and R^(3') may be taken together to form a 5 or 6 membered ring substituted with 0-2 R⁶ ;

R⁴ and R^(4') are independently selected from H, OR³, C₁₋₄ alkyl, phenyl and NR³ R^(3') ;

R⁵ is selected from C₁₋₄ alkyl, phenyl and NR³ R^(3') ;

Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r) O(CH₂)_(r), (CH₂)₂ NR³ (CH₂)_(r), (CH₂)_(r) C(O)(CH₂)_(r), (CH₂)_(r) C(O)O(CH₂)_(r), (CH₂)₂ OC(O)(CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)(CH₂)_(r), (CH₂)₂ OC(O)O(CH₂)_(r), (CH₂)₂ OC(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)O(CH₂)_(r), (CH₂)₂ NR³ C(O)NR³ (CH₂)_(r), (CH₂)_(r) S(O)_(p) (CH₂)_(r), (CH₂)_(r) SO₂ NR³ (CH₂)_(r), (CH₂)₂ NR³ SO₂ (CH₂)_(r), and (CH₂)₂ NR³ SO₂ NR³ (CH₂)_(r) ;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

B is selected from:

X--Y, NR³ R^(3'), C(O)NR³ R^(3'), SO₂ NR³ R^(3'),

benzyl substituted with 0-2 R⁶,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3'), --CR³ R^(3') C(O)--, --C(O)O--, --C(O)OCR³ R^(3') --, --CR³ R^(3') C(O)O--, --OC(O)--, --OC(O)CR³ R^(3') --, --CR³ R^(3') OC(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --S(O)₂ NR³ --, --NR³ S(O)₂ --, --NR³ S(O)₂ CR³ R^(3') --, --CR³ R^(3') S(O)₂ NR³ --, --NR³ S(O)₂ NR³ --, --C(O)NR³ --, --NR³ C(O)--, --C(O)NR³ CR³ R^(3') --, --NR³ C(O)CR³ R^(3') --, --CR³ R^(3') C(O)NR³ --, --CR³ R^(3') NR³ C(O)--, --NR³ C(O)O--, --OC(O)NR³ --, --NR³ C(O)NR³ --, --NR³ --, --NR³ CR³ R^(3') --, --CR³ R^(3') NR³ --, O, --CR³ R^(3') O--, --OCR³ R^(3') --, S, --CR³ R^(3') S--, and --SCR³ R^(3') --;

Y is selected from:

C₁₋₄ alkyl substituted with 0-2 R⁶

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R⁶ is selected from H, OH, CF₃, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), NR³ SO₂ NR³ R^(3'), NR³ SO₂ --C₁₋₄ alkyl, SO₂ -phenyl, and NR³ SO₂ R⁸ ;

R⁷ is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ; and,

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R⁸ is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁹ ; and,

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁹ ;

R⁹ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), NR³ SO₂ NR³ R^(3'), and NR³ SO₂ --C₁₋₄ alkyl;

R¹⁰ is selected from H, OR³, halo, C₁₋₄ alkyl, CN, NO₂, NR³ R^(3'), NR³ C(O)R^(3'), NR³ C(O)OR^(3'), NR³ SO₂ -phenyl, and NR³ SO₂ --C₁₋₄ alkyl;

R^(10a) if a substituent on nitrogen is selected from H and C₁₋₄ alkyl;

R^(10a) if a substituent on carbon is selected from H, C₁₋₄ alkyl, NR³ R^(3'), NR³ C(O)R^(3'), NR³ C(O)OR^(3'), NR³ SO₂ -phenyl, and NR³ SO₂ --C₁₋₄ alkyl;

R¹¹ is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R¹² is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl;

R¹³ is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl;

n is selected from 0, 1, 2, and 3;

m is selected from 0 and 1;

p is selected from 0, 1, and 2;

q is selected from 1, 2, 3, 4, and 5; and

r is selected from 0, 1, and 2.

2! In a preferred embodiment, the present invention provides compounds of formula I wherein:

D is C(═NH)NH₂ ;

D' is H;

R¹ is selected from H, (CH₂)_(r) OR³, halo, (CH₂)_(r) NR⁴ R^(4'), (CH₂)_(r) CO₂ H, (CH₂)_(r) C(═O)R⁴, (CH₂)_(r) NR⁴ C(═O)R⁴, (CH₂)_(r) SO₂ R⁵, and (CH₂)_(r) NHSO₂ R⁵ ;

R² is selected from H, ═O, (CH₂)_(r) OR³, (CH₂)_(r) C(O)R⁴, (CH₂)_(r) OC(O)R⁴, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) NR³ C(O)R⁴, (CH₂)_(r) SO₂ R⁵, (CH₂)_(r) NR³ SO₂ R⁵, C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R⁴ and R^(4') are independently selected from H, OR³, C₁₋₄ alkyl, and NR³ R^(3') ;

R⁵ is selected from C₁₋₄ alkyl and NR³ R^(3') ;

Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r) C(O)(CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)(CH₂)_(r), (CH₂)₂ OC(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)O(CH₂)_(r), (CH₂)₂ NR³ C(O)NR³ (CH₂)_(r), (CH₂)_(r) S(O)_(p) (CH₂)_(r), (CH₂)_(r) SO₂ NR³ (CH₂)_(r), (CH₂)₂ NR³ SO₂ (CH₂)_(r), and (CH₂)₂ NR³ SO₂ NR³ (CH₂)_(r) ; and,

X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3'), --CR³ R^(3') C(O)--, --C(O)O--, --C(O)OCR³ R^(3'), --CR³ R^(3') C(O)O--, --OC(O)--, --OC(O)CR³ R^(3'), --CR³ R^(3') OC(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --S(O)₂ NR³ --, --C(O)NR³ --, --NR³ C(O)--, --NR³ C(O)O--, --OC(O)NR³ --, --NR³ C(O)NR³ --, --NR³ --, --NR³ CR³ R^(3') --, --CR³ R^(3') NR³ --, O, --CR³ R^(3') O--, and --OCR³ R^(3') --.

3! In a more preferred embodiment, the present invention provides compounds of formula I wherein:

R¹ is selected from H, OR³, (CH₂)OR³, halo, NR⁴ R^(4'), (CH₂)NR⁴ R^(4'), C(═O)R⁴, (CH₂)C(═O)R⁴, NHC(═O)R⁴, (CH₂)NHC(═O)R⁴, SO₂ R⁵, (CH₂)SO₂ R⁵, NHSO₂ R⁵, and (CH₂)NHSO₂ R⁵ ;

R² is selected from H, ═O, OR³, C(O)R⁴, (CH₂)C(O)R⁴, OC(O)R⁴, NR⁴ R^(4'), NR³ C(O)R⁴, and NR⁴ SO₂ R⁵ ;

A is selected from:

C₅₋₆ carbocyclic residue substituted with 0-1 R⁶, and

5-6 membered heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N and O substituted with 0-1 R⁶ ;

B is selected from: Y, X--Y, and NR² R^(2a) ;

Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a) ;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, isoindazole, and benzothiadiazole;

Y may also be selected from the following bicyclic heteroaryl ring systems: ##STR11## K is selected from O, S, NH, and N; X is selected from --CH₂ --, --C(O)--, --C(O)CHR³ --, --CHR³ C(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CHR³ S(O)_(p) --, --S(O)₂ NR³ --, --C(O)NR³ --, --NR³ C(O)--, --NR³ --, --NR³ CHR³ --, and --CHR³ NR³ ;

R⁶ is selected from H, OH, CF₃, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), SO₂ NR³ R^(3'), SO₂ -phenyl, NR³ SO₂ --C₁₋₄ alkyl, and NR³ SO₂ R⁸ ;

R⁸ is selected from:

C₅₋₆ carbocyclic residue substituted with 0-2 R⁹ ; and,

5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁹ ;

R⁹ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), NR³ SO₂ NR³ R^(3'), and NR³ SO₂ --C₁₋₄ alkyl; and,

p is 2.

4! In an even more preferred embodiment, the present invention provides compounds of formula I wherein:

Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r) C(O)(CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)(CH₂)_(r), (CH₂)₂ NR³ C(O)NR³ (CH₂)_(r), and (CH₂)_(r) S(CH₂)_(r) ;

X is selected from --CH₂ --, --C(O)--, --C(O)CHR³ --, --CHR³ C(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CHR³ S(O)_(p) --, --S(O)₂ NR³ --, --C(O)NR³ --, and --NR³ C(O)--;

R⁶ is selected from H, OH, CF₃, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), SO₂ NR³ R^(3'), SO₂ -phenyl, and NR³ SO₂ --C₁₋₄ alkyl;

m is 1; and,

r is selected from 0 and 1.

5! In a further preferred embodiment, the present invention provides compounds of formula I wherein:

R³ and R^(3') are independently selected from H and C₁₋₄ alkyl;

Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)(CH₂)_(r), and (CH₂)₂ NR³ C(O)NR³ (CH₂)_(r) ;

A is selected from phenyl substituted with 0-1 R⁶ and a 6 membered heterocyclic system containing 1 N and 0-1 O atoms and substituted with 0-1 R⁶ ;

X is selected from --CH₂ --, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --S(O)₂ NR³ --, --C(O)NR³ --, and;

Y is selected from phenyl, i-propyl, quinolynyl, thiadizolyl, benzothiadiazolyl, thiophenyl, pyridyl, cyclohexyl, and naphthyl, each of which is substituted with 0-2 R⁶ ; and,

n is selected from 0, 1, and 2.

6! In an even further preferred embodiment, the present invention provides compounds of formula I wherein:

R³ and R^(3') are independently selected from H and methyl;

Z is selected from a bond, CH₂, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ -- and --CH₂ CH₂ CH₂ CH₂ --;

A is selected from phenyl substituted with 0-1 R⁶, and piperidinyl substituted with 0-1 R⁶ ; and,

n is 2.

7! In a particularly preferred embodiment, the present invention provides compounds selected from:

N-(3-amidinophenyl)-N'-((4-((2-sulphonamido)phenyl)phenyl)methyl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(picolin-2-yl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(picolin-3-yl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(picolin-4-yl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(a-phenethyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((phenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(phenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(quinolin-8-yl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(2-fluorophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(4-acetamidophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(3-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(4-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((2-aminophenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((2-acetamido-phenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((thiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((5-chlorothiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((5-carbomethoxythiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((benzo-2,1,3-thiadiazo-4-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((cyclohexyl)sulfamido)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((isopropyl)sulfamido)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((phenyl)sulfamido)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((isopropyl)sulfonyl)-piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((5-amino-4-methylthiazol-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((5-acetamido-4-methylthiazol-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(6-carbomethoxyphenylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(2-pyridylmethyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(3-pyridylmethyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(4-pyridylmethyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(phenyl-N"-methylsulfamido)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-((4-phenylsulfonylthiophen-2-yl)sulfonyl)-piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(4-pyridylmethylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(thiophen-2-ylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(4-fluorobenzylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(2-pyridylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(2-trifluormethylphenylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(2-phenylisopropylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-((1-((phenyl)-1,1-dimethyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(methyl((phenylmethane)carbamide)morpholin-3-yl))cycloheptylurea;

N-(3-amidinophenyl)-N'-(methyl((thiophen-2-yl)sulfonyl)morpholin-3-yl))cycloheptylurea;

N-(3-amidinophenyl)-N'-(methyl((phenylmethane)sulfonyl)morpholin-3-yl))cycloheptylurea;

N-(3-amidinophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-((N-(benzyl)sulfonyl)-piperidin-3-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(4-(2-sulfonamidophenyl)phenyl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(5-(2-sulfonamido-phenyl)pyridin-2-yl)cycloheptylurea; and,

N-(3-amidinophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea;

or stereoisomers or pharmaceutically acceptable salt forms thereof.

8! In another preferred embodiment, the present invention provides compounds wherein:

n is 2; and,

R² and R^(2a) are on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R¹⁰ or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 R^(10a).

9! In another more preferred embodiment, the present invention provides novel compounds of formula II: ##STR12## or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein;

ring N contains 0-2 N atoms and is substituted with 0-2 R¹⁰ ; and,

D is selected from CN, C(═NR¹¹)NR¹² R¹³, NHC(═NR¹¹)NR¹² R¹³, NR¹² CH(═NR¹¹), C(O)NR¹² R¹³, and (CH₂)_(t) NR¹² R¹³.

10! In another even more preferred embodiment, the present invention provides compounds of formula II wherein:

D is C(═NH)NH₂ ;

R¹ is selected from H, (CH₂)_(r) OR³, halo, (CH₂)_(r) NR⁴ R^(4'), (CH₂)_(r) CO₂ H, (CH₂)_(r) C(═O)R⁴, (CH₂)_(r) NR⁴ C(═O)R⁴, (CH₂)_(r) SO₂ R⁵, and (CH₂)_(r) NHSO₂ R⁵ ;

R⁴ and R^(4') are independently selected from H, OR³, C₁₋₄ alkyl, and NR³ R^(3') ;

R⁵ is selected from C₁₋₄ alkyl and NR³ R^(3') ;

Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r) C(O)(CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)(CH₂)_(r), (CH₂)₂ OC(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)O(CH₂)_(r), (CH₂)₂ NR³ C(O)NR³ (CH₂)_(r), (CH₂)_(r) S(O)_(p) (CH₂)_(r), and (CH₂)_(r) SO₂ NR³ (CH₂)_(r) ; and,

X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O)--, --C(O)O--, --C(O)OCR³ R^(3') --, --CR³ R^(3') C(O)O--, --OC(O)--, --OC(O)CR³ R^(3') --, --CR³ R^(3') OC(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --C(O)NR³ --, --NR³ C(O)--, --NR³ C(O)O--, --OC(O)NR³ --, --NR³ C(O)NR³ --, --NR³ --, --NR³ CR³ R^(3') --, --CR³ R^(3') NR³ --, O, --CR³ R^(3') O--, and --OCR³ R^(3') --.

11! In another further preferred embodiment, the present invention provides compounds of formula II, wherein:

Z is selected from a bond, C₁₋₄ alkylene, C(O)NR³ (CH₂)_(r), S(O)₂, S(O)₂ CH₂, and (CH₂)_(r) SO₂ NR³ (CH₂)_(r) ;

A is selected from phenyl substituted with 0-1 R⁶ and 6 membered heterocyclic system containing 1 N and substituted with 0-1 R⁶ ; and,

X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3'), --CR³ R^(3') C(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --C(O)NR³ --, and, --NR³ --.

12! In another even further preferred embodiment, the present invention provides compounds selected from:

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;

1,2,4,5-tetrahydro-2-(thiopen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one; and,

1,2,4,5-tetrahydro-2-(thiophen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one.

In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.

In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, "C₁₋₆ alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; 3.3.0!bicyclooctane, 4.3.0!bicyclononane, 4.4.0!bicyclodecane (decalin), 2.2.2!bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, benzothiadiazolyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro 2,3-b!tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C(═NR¹¹)NH₂, and R¹¹ is selected from OH, C₁₋₄ alkoxy, C₆₋₁₀ aryloxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, and C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl. More preferred prodrugs are where R¹¹ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

SYNTHESIS

Compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference. All the temperatures are reported herein in degrees Celsius.

The compounds of Formula 1 can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

Two general approaches can be used for the preparation of the cyclic ureas of this invention. The first involves bimolecular cyclizations to the cyclic urea, as outlined in Scheme I, the second uses the internal unimolecular cyclizations of Scheme II. ##STR13##

Route A of Scheme I illustrates the bis-alkylation of an N,N'-disubstituted urea with an alkane substituted at both termini with an appropriate leaving group (L.G.), such as a halogen or sulfonate ester. The flexibility of this approach also allows for the bis-alkylation with an alkene or R² -substituted alkane which is again substituted at both termini with an appropriate leaving group (L.G.). Such alkylation agents are either commercially available, e.g. 1,4-dibromobutane and its lower homologs, found in the literature, e.g. the isopropylidene ether of 1,4-diiodido-2,3-dihydroxybutane (Deluca and Magnus, J. Chem. Soc. (Perkin Trans. I), 2661(1991), and Hoye and Suhadolnik, Tetrahedron, 42 (11) 2855 (1986)), or can be prepared by a practitioner skilled in the art using standard chemical methods.

The N,N'-disubstituted urea can be generated from two primary amines, one of which must be a Q,R¹ -substituted aniline wherein Q is a functional group from which an amidine could be readily generated such as nitrile; in some special cases Q may be tolerated as a mono- or di- acyl or carbamoyl protected amidine. The second primary amine, H₂ N--Z--A--B, may be any amine deemed appropriate within the limits of Formula 1. This amine may be commercially available, e.g. 1-benzyl-4-aminopiperidine, found in the literature, e.g. 1-t-butoxycabonyl-4-aminopiperidine (Mach et al., J. Med. Chem., 36(23), 3707 (1993)), or can be prepared by a practitioner skilled in the art utilizing standard chemical methods.

The two primary amines described above can be assembled to the desired N,N'-disubstituted urea by selecting one for transformation to the corresponding isocyanate in situ by stirring with phosgene or its equivalent such as trichloromethyl chloroformate or p-nitrophenylchloroformate in the presence of a trialkylamine base and a dry, aprotic solvent such as dimethylformamide, dioxane, benzene or a chlorinated alkane. The temperature of this reaction may be varied from -10° C. to the reflux point of the solvent (Takeda et al., Tetrahedron Lett., 24(42) 4569 (1983), Cortez et al., Synth. Commun., 21(2) 285 (1991)). Alternatively the desired isocyanate may be commercially available, such as 3-cyanophenyl isocyanate, in which case convenience dictates that this substrate be used. Conditions for direct reaction of a preformed isocyanate are similar to those described above with the caveat that the phosgene equivalent is necessary, and the trialkylamine base may be omitted (Shiau et al., J. Heterocyclic Chem., 26, 595(1989)).

Ring formation in Route A is achieved by alkylation of the N,N'-disubstituted urea with the dihalogenated (Curtis, Aust. J. Chem., 41 585 (1988), Htay et al., Tetrahedron Lett., 79 (1976), Sulsky et al., Synth. Commun., 19, 1871 (1989)) or disulfonated (Ayyana et al., Chem. Ind. (London), 599 (1988)) alkylating agent described above. Typically, the disubstituted urea is added at ambient temperature or lower to a mixture of at least two equivalents of strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium in an appropriate anhydrous solvent such as tetrahydrofuran, dimethylformamide, t-butanol, toluene or dimethylsulfoxide. After deprotonation is complete, a solution of the alkylating agent in the selected solvent is added slowly to the disubstituted urea at ambient temperature or lower; when the addition is completed, the reaction may be continued at ambient temperature or lower or heated up to the reflux temperature of the solvent, depending upon the reactivity of the alkylating agent/disubstituted urea pair and the patience of the practitioner.

Route B of Scheme I illustrates use of an appropriately substituted diamine and phosgene or its equivalent to generate a cyclic urea precursor to Formula 1. The required diamine can be generated by two approaches. The first approach utilizes a Q,R¹ -substituted aniline which is conjoined with an N-acyl or N-carbamoyl protected secondary amine where G is a halogen or sulfonate ester leaving group for a standard alkylation of the Q,R¹ -substituted aniline or G could be an aldehyde suitable for reductive alkylation of the Q,R¹ -substituted aniline. The second approach to diamine formation conjoins an N-acyl or N-carbamoyl protected N-alkylated Q,R¹ -substituted aniline, where G is as described above, with primary amine H₂ N--Z--A--B by a standard or reductive alkylation.

Both protected secondary amines are available by similar chemistry. The selected aniline or primary amine H₂ N--Z--A--B is protected with a N-acyl or N-carbamoyl protecting group according to a method specified in Greene and Wuts; N-t-butoxy carbamoyl is useful for this application. This protected amine can then be cleanly mono-alkylated with one of the dihalogenated or disulfonylated alkylating agents recommended for Route A (Reed et al., Tetrahedron Lett., 79(45) 5725 (1988)). Alternatively, the protected amine can be mono-alkylated with a protected halo alcohol. Both alkylations are readily achieved in anhydrous aprotic solvents such as toluene, tetrahydrofuran, dimethylformamide or dimethylsulfoxide at temperatures ranging from -78° C. to the reflux temperature of the selected solvent with a strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium. In the case where G is a protected alcohol, the protecting group is removed and an aldehyde generated by Moffatt oxidation (Pfitzner and Moffatt, J. Amer. Chem. Soc., 87 5661 (1965)) or through use of pyridinium chlorochromate (Corey and Suggs, Tetrahedron Lett., 2647 (1975)) or pyridinium dichromate in dichloromethane (Coates and Corrigan, Chem. Ind. (London), 1594 (1969)).

The required diamine can then be prepared by stirring the alkylating agent with the primary amine component either neat or in an aprotic solvent such as toluene, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. The temperature of this reaction may range from -78° C. to the reflux temperature of the selected solvent. A strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium or a weaker trialkylamine base may be used, depending upon the reactivity of the two components. As an alternative, when G is an aldehyde, a reductive alkylation of the primary amine component is possible. The direct method involves the use of a borohydride reducing agent, most preferably sodium or lithium cyanoborohydride, in a mixture of aldehyde and amine components in an alcoholic solvent (Borch et al., J. Amer. Chem. Soc., 93 2897 (1971)). A stepwise method involves generation of an intermediate imine/enamine by azeotropic removal of water from a heated mixture of aldehyde and primary amine component in a suitable solvent such as benzene at reflux temperature. The imine/enamine intermediate can then be isolated and reduced by palladium catalyst under an atmosphere of hydrogen gas at ambient pressure or higher or reduced by borohydride reagents under conditions similar to those preferred for the direct method. The required diamine is generated by removal of the protecting group according to a method recommended in Greene and Wuts.

The diamine formed above is reacted with phosgene or its equivalent such as trichloromethyl chloroformate or p-nitrophenylchloroformate in the presence of an excess of a trialkylamine base and a dry, aprotic solvent such as dimethylformamide, dioxane, toluene, benzene or a chlorinated alkane to form a cyclic urea precursor to Formula 1. The temperature of this reaction may be varied from -10° C. to the reflux point of the solvent. ##STR14##

Two alternatives, Route C and Route D, for the preparation of precursors of Formula 1 by a unimolecular cyclization method are outlined in Scheme II. In Route C one begins by alkylating a Q,R¹ -substituted aniline with a halogenated alkylalcohol, such as 4-bromobutan-1-ol or its homologs, or a protected version of the same, such as the methoxymethyl ether of 4-bromobutan-1-ol, either neat or in an anhydrous solvent such as dimethylformamide, benzene, tetrahydrofuran, hexamethylphosphorotriamide, or dimethylsulfoxide. This reaction may be furthered by heating the mixture up to the reflux point of the solvent. Depending upon the reactivity of the substrate no base, or a strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium, or a weak base, such as potassium carbonate or a trialkylamine, may be necessary. The alkylation product is then reacted with an isocyanate OCN--Z--A--B generated from the amine NH₂ --Z--A--B by the same method described above for Route A of Scheme I to give a product alcohol or protected alcohol which can be transformed to a halogenated or sulfonyl ester analog for cyclization to a cyclic urea precursor to Formula 1.

Following deprotection according to an appropriate method found in Greene and Wuts (if necessary), halogenation of the primary alcohol can be carried out with a variety of reagents such as neat thionyl chloride, triphenylphosphine in carbon tetrachloride (Lee and Downie, Tetrahedron, 23 359 (1967)), or triphenylphosphine with N-chloro- or N-bromosuccinimide in dimethylformamide. The alternative sulfonyl ester is also readily prepared from an appropriate sulfonyl chloride, such as the commercially available p-toluenesulfonyl chloride or methanesulfonyl chloride, in a variety of anhydrous aprotic solvents, such as pyridine, benzene, tetrahydrofuran or a chlorinated hydrocarbon, with or without cooling, and with or without a trialkylamine base.

Ring closure to a cyclic urea precursor to Formula 1 has been observed to occur spontaneously in some cases, but may be furthered in an anhydrous solvent such as dimethylformamide, benzene, tetrahydrofuran, hexamethylphosphorotriamide, or dimethylsulfoxide, by heating the mixture up to the reflux point of the solvent. Depending upon the reactivity of the substrate no base, or a strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium, or a weak base, such as potassium carbonate or a trialkylamine, may be necessary.

Route D of Scheme II may be advantageous over Route C for the availability of starting materials such as the commercially produced 1-benzyl-4-aminopiperidine for NH₂ --Z--A--B component, 2-bromoethanol for the halo alcohol component, and 3-cyanophenyl isocyanate for the isocyanate component. In any respect, the chemistry described in Route C is applicable to an analogous reaction in Route D with modifications appropriate for the particular materials involved.

In Formula 1 the radical Z serves as a linking group interposed between the cyclic urea structure and radical A--B. For the purposes of this discussion it is recognized that there are variations of Z, that is where Z=a bond or C₁₋₄ alkylene or a portion of the defined linkage, that for synthetic purposes are best incorporated as a substituent of A. It is also assumed for the purpose of this discussion that the analog of A used throughout may contain an orthogonal protecting group, which is compatible with the chemistry suggested. Furthermore, this protecting group may be removed to reveal a substituent that can be used to generate a group X. ##STR15##

The preparation of Z outlined in Scheme III begins with the O-protected derivative of 2-aminoethanol. The t-butyldimethylsilyl analog is recommended for this purpose and is know in the literature (see WO 9504277 and WO 9205186). However, a worker skilled in the art would recognize that the approaches discussed herein are not limited to this particular analog of 2-aminoethanol. O-Protected 2-aminoethanol can then be protected as the N-t-butoxycarbonyl analog and selectively O-deprotected according to procedures found in Greene and Wuts. The resulting 2-(N-t-butoxycarbamoyl)ethanol (1) can then be reacted with various analogs of A to give the desired group Z.

Product 2 is the result of reaction of the chlorocarbonate analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° to ambient temperature. The carbonyl chloride analog of A (A(CH₂)_(r) OC(O)Cl) is avaialable by reaction of an appropriate alcohol analog of A with phosgene or one of its equivilents in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° to ambient temperature.

Product 3 is prepared by reaction of the acid chloride of an appropriate acid analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° to ambient temperature. The acid chloride can be obtained by reaction of the acid analog of A with phosphorous oxychloride, phosphorous pentachloride, thionyl chloride or oxalyl chloride with or without a non-polar aprotic solvent such as a chlorocarbon, benzene or toluene at temperatures ranging from 0° C. to the reflux point of the solvent or neat reagent.

Product 4 can be prepared by the reaction of a carbamoyl chloride analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° C. to ambient temperature. The carbamoyl chloride analog of A (A(CH₂)_(r) NR³ C(O)Cl) is avaialable by reaction of an appropriate amine analog of A with phosgene or one of its equivilents in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° C. to ambient temperature.

Product 5 is available by the reaction of an analog of A substituted with an appropriate leaving group with the alkoxide generated from 2 by treatment of 2 with a stong base such as sodium or potassium hydride or a thallium alkoxide in an aprotic solvent such as dimethylformamide, tetrahydrofuran or dimethylsulfoxide at a temperature ranging from 0 to 120° C. The leaving group of A is most conviently generated from an appropriate alcohol analog of A. The alcohol function can be used to prepare a sulfonate ester from a sulfonyl chloride in a cholorocarbon solvent with a trialkylamine base or in pyridine; alternatively the halogen can be generated from a variety of reagents, triphenyl phosphine and carbon tetrabromide, phosphorous pentabromide or chloride, and thionyl chloride, to name a few. ##STR16##

The series of analogs in Scheme IV can be prepared from the protected amino alcohol 6 to give products 7 to 12 by methods similar to some of those described for Scheme III. Compound 6 is prepared from 2-amino-(O-t-butyldimethylsilyl)ethanol by reductive amination of the primary amine by a variety of methods. The primary amine may be reacted with an aldehyde or ketone under dehydrating conditions to form an imine or enamine intermediate which is then reduced to the N-alkyl derivative using palladium catalyst under an atmosphere of hydrogen in an appropriate solvent. Alternatively, reductive alkylation can be effected by a mixture of the ketone or aldehyde and the amine with lithium or sodium cyanoborohydride in methanol or ethanol as solvent.

It is to be understood that products 7 to 12 need to have the terminal protected oxygen transformed to the primary amine either at this stage or after elaboration with group B. This can conveniently be achieved by deprotection of the primary alcohol. The alcohol function can then be used to prepare a sulfonate ester from a sulfonyl chloride in a chlorocarbon solvent with a trialkylamine base or in pyridine; alternatively a halogen can be generated from a variety of reagents, triphenyl phosphine and carbon tetrabromide, phosphorous pentabromide or chloride, and thionyl chloride, to name a few. The resulting leaving group is then displaced with a mixture of sodium azide in dimethylformamide at an elevated temperature to form the primary azide. The azide can then be reduced to the amine by catalytic hydrogenation in an alcoholic solvent with palladium catalyst under an atmosphere of hydrogen gas at pressures ranging from ambient to 65 psi; an alternative method for effecting this transformation involves refluxing the azide intermediate with triphenylphosphine in benzene or toluene and hydrolyzing the resulting intermediate with aqueous acid.

Product 7 of Scheme IV is the result of the reaction of the chlorocarbonate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° C. to ambient temperature. Product 8 is prepared by the reaction of the acid chloride of an appropriate acid analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° C. to ambient temperature. Product 9 can be prepared by the reaction of a carbamoyl chloride analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° to ambient temperature.

Product 10 may be obtained from 7 by two routes, conventional alkylation or reductive alkylation. If 6 is a primary amine, then reductive alkylation is recommended. The primary amine 6 may be reacted with an aldehyde or ketone analog of A under dehydrating conditions to form an imine or enamine intermediate which is then reduced to the N-alkyl derivative using palladium catalyst under an atmosphere of hydrogen in an appropriate solvent. Alternatively, reductive alkylation can be effected by a mixture of the ketone or aldehyde and the amine with lithium or sodium cyanoborohydride in methanol or ethanol as solvent. The aldehyde or ketone analog of A is readily accessible from the appropriate alcohol by Swern, Moffat or Jones oxidation. In the case where 6 is a secondary amine product 10 is available by the reaction of an analog of A substituted with an appropriate leaving group with 7 in the presence of a weak base such as a trialkylamine or solid sodium or potassium carbonate in an aprotic solvent such as dimethylformamide, acetone, tetrahydrofuran or dimethylsulfoxide at a temperature ranging from 0° to 120° C.

Product 11 is prepared by the reaction of the sulfonyl chloride of an appropriate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° to ambient temperature. The sulfonyl chloride analog of A is available via the sulfonic acid of A which can be prepared by heating a halogen analog of A in a aqueous sodium sulfite. The sulfonyl chloride of A can be prepared by reacting the sulfonic acid with phosphorous oxychloride, phosphorous pentachloride, thionyl chloride or oxalyl chloride with or without a non-polar aprotic solvent such as a chlorocarbon, benzene or toluene at temperatures ranging from 0° C. to the reflux point of the solvent or neat reagent. Product 12 is prepared by the reaction of the sulfamoyl chloride of an appropriate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78° C. to ambient temperature. ##STR17##

Scheme V outlines the preparation of variations of Z that are not readily prepared by the strategies in Schemes III and IV. Compound 13 is available by the routes developed in Schemes I and II by replacing the primary amine NH₂ ZAB with O-t-butyldimethylsilyl-2-aminoethanol or its propanol homolog. Jones oxidation of 13 gives corresponding carboxylic acid which is then transformed to the acid chloride 14 by one of the methods outlined in the preceding discussion. The ester 15 is prepared by reaction of 14 with an alcohol derivative of A under conditions similar to those detailed for the preparation of ester 2 in Scheme III. The amide 16 is available by the reaction of 14 with an amine derived from A under conditions similar to those used for the formation of amide 8 found in Scheme IV. The sulfonyl chloride 17 of Scheme V is prepared by the alcohol to halide to sulfonic acid to sulfonyl chloride route discussed for the sulfonyl analogs of Scheme IV. Reaction of 17 with an amine derivative of A under conditions used for the formation of 11 in Scheme IV gives the sulfonamide 18 of Scheme V. ##STR18##

In Scheme VI two approaches to the incorporation of group B are outlined; in each case it is assumed that the starting structures are suitably protected to accommodate the chemistry that follows. It is also understood that both approaches may not be equivilent and, for purposes of compatibility with the chemistry that follows, one approach may have certain advantages over the other. It is further assumed that groups A and B have been selected to be derivatives of A and B that contain functionality suitable for the chemistry contemplated. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.

                                      TABLE 1     __________________________________________________________________________     Preparation of Amide, Ester, Urea, Sulfonamide and     Sulfamide linkages between A and B.                    then the reactive                              to give the     Rxn.           substituent of                              following product     No. if A contains:                    Y is:     A--X--Y:     __________________________________________________________________________     1   A--NHR.sup.3 as a                    ClC(O)--Y A--NR.sup.3 --C(O)--Y         substituent     2   a secondary NH                    ClC(O)--Y A--C(O)--Y         as part of a         ring or chain     3   A--OH as a ClC(O)--Y A--O--C(O)--Y         substituent     4   A--NHR.sup.3 as a                    ClC(O)--CR.sup.3 R.sup.3' --Y                              A--NR.sup.3 --C(O)--CR.sup.3 R.sup.3' --Y         substituent     5   a secondary NH                    ClC(O)--CR.sup.3 R.sup.3'--Y                              A--C(O)--CR.sup.3 R.sup.3' --Y         as part of a         ring or chain     6   A--OH as a ClC(O)--CR.sup.3 R3'--Y                              A--O--C(O)--CR.sup.3 R.sup.3' --Y         substituent     7   A--NHR.sup.3 as a                    ClC(O)NR.sup.3 --Y                              A--NR.sup.3 --C(O)NR.sup.3 --Y         substituent     8   a secondary NH                    ClC(O)NR.sup.3 --Y                              A--C(O)NR.sup.3 --Y         as part of a         ring or chain     9   A--OH as a ClC(O)NR.sup.3 --Y                              A--O--C(O)NR.sup.3 --Y         substituent     10  A--NHR.sup.3 as a                    ClSO.sub.2 --Y                              A--NR.sup.3 --SO.sub.2 --Y         substituent     11  a secondary NH                    ClSO.sub.2 --Y                              A--SO.sub.2 --Y         as part of a         ring or chain     12  A--NHR.sup.3 as a                    ClSO.sub.2 --CR.sup.3 R.sup.3' --Y                              A--NR.sup.3 --SO.sub.2 --CR.sup.3 R.sup.3' --Y         substituent     13  a secondary NH                    ClSO.sub.2 --CR.sup.3 R.sup.3' --Y                              A--SO.sub.2 --CR.sup.3 R.sup.3' --Y         as part of a         ring or chain     14  A--NHR.sup.3 as a                    ClSO.sub.2 --NR.sup.3 --Y                              A--NR.sup.3 --SO.sub.2 --NR.sup.3 --Y         substituent     15  a secondary NH                    ClSO.sub.2 --NR.sup.3 --Y                              A--SO.sub.2 --NR.sup.3 --Y         as part of a         ring or chain     16  A--C(O)Cl  HO--Y as a                              A--C(O)--O--Y                    substituent     17  A--C(O)Cl  NHR.sup.3 --Y as a                              A--C(O)--NR.sup.3 --Y                    substituent     18  A--C(O)Cl  a secondary NH as                              A--C(O)--Y                    part of a ring or                    chain     19  A--CR.sup.3 R.sup.3' C(O)Cl                    HO--Y as a                              A--CR.sup.3 R.sup.3' C(O)--O--Y                    substituent     20  A--CR.sup.3 R.sup.3' C(O)Cl                    NHR.sup.3 --Y as a                              A--CR.sup.3 R.sup.3' C(O)--NR.sup.3 --Y                    substituent     21  A--CR.sup.3 R.sup.3' C(O)Cl                    a secondary NH as                              A--C(R.sup.3).sub.2 C(O)--Y                    part of a ring or                    chain     22  A--SO.sub.2 Cl                    NHR.sup.3 --Y as a                              A--SO.sub.2 --NR.sup.3 --Y                    substituent     23  A--SO.sub.2 Cl                    a secondary NH as                              A--SO.sub.2 --Y                    part of a ring or                    chain     24  A--CR.sup.3 R.sup.3' SO.sub.2 Cl                    NHR.sup.3 --Y as a                              A--CR.sup.3 R.sup.3' SO.sub.2 --NR.sup.3 --Y                    substituent     25  A--CR.sup.3 R.sup.3' SO.sub.2 Cl                    a secondary NH as                              A--CR.sup.3 R.sup.3' SO.sub.2 --Y                    part of a ring or                    chain     __________________________________________________________________________

The chemistry of Table 1 can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20° C. to the reflux point of the solvent and with or without a trialkylamine base.

                                      TABLE 2     __________________________________________________________________________     Preparation of ketone linkages between A and B.                    then the reactive                               to give the     Rxn.           substituent of                               following product     No.  if A contains:                    Y is:      A--X--Y:     __________________________________________________________________________     1    A--C(O)Cl BrMg--Y    A--C(O)--Y     2    A--CR.sup.3 R.sup.3' C(O)Cl                    BrMg--Y    A--CR.sup.3 R.sup.3' 2C(O)--Y     3    A--C(O)Cl BrMgCR.sup.3 R.sup.3' --Y                               A--C(O)CR.sup.3 R.sup.3' --Y     4    A--CR.sup.3 R.sup.3' C(O)Cl                    BrMgCR.sup.3 R.sup.3' --Y                               A--CR.sup.3 R.sup.3' C(O)CR.sup.3 R.sup.3' --Y                               Y     __________________________________________________________________________

The coupling chemistry of Table 2 can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0° C. to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temperature (-20° C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide.dimethyl sulfide complex in dimethyl sulfide as a solvent or with a varient thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)₃ according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).

                  TABLE 3     ______________________________________     Preparation of ether and thioether linkages between     A and B                        then the reactive                                     to give the     Rxn.               substituent of                                     following     No.   if A contains:                        Y is:        product A--X--Y:     ______________________________________     1     A--OH        Br--Y        A--O--Y     2     A--CR.sup.3 R.sup.3' --OH                        Br--Y        A--CR.sup.3 R.sup.3' 0--Y     3     A--OH        Br--CR.sup.3 R.sup.3' --Y                                     A--OCR.sup.3 R.sup.3' --Y     4     A--SH        Br--Y        A--S--Y     5     A--CR.sup.3 R.sup.3' --SH                        Br--Y        A--CR.sup.3 R.sup.3' S--Y     6     A--SH        Br--CR.sup.3 R.sup.3' --Y                                     A--SCR.sup.3 R.sup.3' --Y     ______________________________________

The ether and thioether linkages of Table 3 can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.

                  TABLE 4     ______________________________________     Preparation of --SO-- and --SO.sub.2 -- linkages from     thioethers of Table 3.                                    and it is oxidized                      and it is oxidized                                    with m-chloroper-                      with Alumina (wet)/                                    benzoic acid (Satoh          if the      Oxone (Greenhalgh,                                    et al., Chem. Lett.     Rxn. starting    Synlett, (1992) 235)                                    (1992) 381, the     No.  material is:                      the product is:                                    product is:     ______________________________________     1    A--S--Y     A--S(O)--Y    A--SO.sub.2 --Y     2    A--CR.sup.3 R.sup.3' S--Y                      A--CR.sup.3 R.sup.3' --S(O)--Y                                    A--CR.sup.3 R.sup.3' SO.sub.2 --Y     3    A--SCR.sup.3 R.sup.3' --Y                      A--S(O)CR.sup.3 R.sup.3' --Y                                    A--SO.sub.2 CR.sup.3 R.sup.3' --Y     ______________________________________

The thioethers of Table 3 serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table 4. A combination of wet alumina and oxone provides a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone. ##STR19##

A cyclic urea precursor of Formula 1 which is suitable for the preparation of analogs where Z=--C(O)-- or --SO₂ -- can be synthesized by an adaptation of the chemistry outlined in Scheme I. The approach in Scheme VII makes use of a N-hydrazino-alkylbromide as the alkylating agent for the aniline derivative. The alkylation product is then deprotected according to a method proscribed by Greene and Wutts and cyclized by treatment of the resulting diamine with phosgene or one of its equivilents. The resulting cyclic urea can be treated with a strong base such as sodium hydride or potassium t-butoxide in an aprotic solvent like dimethyl formamide, dimethylsulfoxide or toluene. This mixture is quenched with an acid chloride or sulfonyl chloride analog of A--B at a temperature ranging from -78° C. to the reflux point of the solvent. ##STR20##

The final transformation of the cyclic urea precursor of Formula 1 prepared in Schemes I to VII to Formula 1 is outlined in Scheme VIII. The preferred method was first described by Pinner and Klein (Ber,, 10, 1889 (1877); for a more recent review see: Decroix, J. Chem. Res., 134 (1978)). By this method the nitrile is dissolved in an anhydrous alcohol or a mixture of 1 equivalent or greater of an alcohol and an anhydrous aprotic co-solvent such as a chlorohydrocarbon or an acetate ester of the selected alcohol (i.e., methyl acetate for methyl alcohol). Typically, this mixture is cooled below ambient temperature and dry hydrogen chloride gas is added slowly to the reaction mixture until the solvent is saturated. This saturated solution is sealed and stirred at ambient temperature or lower to form an imidate intermediate which is isolated and characterized. The imidate is then dissolved in a dry alcohol solvent and excess ammonia in the form of a gas, a standardized ammonia/alcohol solution, solid ammonium acetate or ammonium carbonate is added. The crude compound is conveniently purified by reverse phase HPLC or recrystallization to give the cyclic urea defined by Formula 1.

Scheme IX outlines the general route for the preparation of 5-membered aryl- or heteroaryl-fused examples of Formula II. The preparation of the biaryl amine intermediate can be accomplished by the palladium catalyzed coupling of the substituted aniline to the triflate ester according to the method of Louie et. al., (J. Org. Chem.1997, 62, 1268-1273). ##STR21##

The aniline nitrogen can then be protected as a carbamate, the nitro group reduced to the amine. This amine can be coupled with a Z--A--B group in which Z incorporates a carbonyl group, such as an aldehyde, which can be used as a reactive partner in a reductive alkylation of the newly generated amine. The resulting intermediate can then be processed according to the art described for Route B of Scheme I. ##STR22##

The steps which can be used for the regiocontrolled preparation of both isomers of the 6-membered aryl- or heteroaryl-fused examples of Formula II is outline in Routes A and B of Scheme X. One regioisomer is available by applying the chemistry developed by Louie et al. to the triflate of the salicylate ester in Route A. Following protection of the resulting biaryl amine, the ester can be reduced by lithium borohydride or some other compatible hydride reducing agent and then processed further as outline in Route B of Scheme I.

The alternative regioisomer of Formula II contemplated by this invention can be prepared according to Route B of Scheme X. To effect the palladium catalyzed coupling of the H₂ N--Z--A--B group with the triflate salicylate ester the conditions reported by Wolfe and Buchwald (Pd(OAc)₂, BiNAP, NaO--t-Bu, toluene; J. Org. Chem. 1997, 62, 1264-1267) are optimal. The amine coupling product is then suitably N-protected and the ester functionality is reduce to the benzylic alcohol. This intermediate is then treated further according to the methods outlined in Scheme I, Route B. ##STR23##

Scheme XI describes the route used to prepare a precursor to one regioisomer of the 7-membered aryl- or heteroaryl-fused example of Formula II. The point of departure is usually the 2-cyano substituted aryl- or heteroaryl-ester. Lithium aluminum hydride reduction of these compounds leads to the corresponding amino alcohol which can then be selectively O-protected with a silyl protecting group, preferably the t-butyl dimethylsilyl group. This material is now ready for reductive alkylation by a Z--A--B group in which Z-- contains a carbonyl compound such as an aldehyde, ketone or cyclic ketone. In our experience this transformation can best be performed using a mixture of sodium cyanoborohydride and zinc chloride in tetrahydrofuran solvent. Following reductive alkylation the resulting secondary amine is reacted with an aryl isocyanate in an inert solvent such as dimethylformamide. The isocyanate addition product can then be O-deprotected, and the benzylic alcohol be transformed to the benzylic chloride with a mixture of methanesulfonyl chloride and triethylamine in chloroform or dichloromethane. The benzylic chloride is then cyclized to the 7-membered ring precursor to Formula II with sodium hydride in dimethylformamide at 0° C. ##STR24##

Routes to alternative regioisomers for 7-membered aryl- or heteroaryl-fused examples of Formula II are demonstrated in Scheme XII. In Route A, the phenethylnitro triflate can undergo a palladium catalyzed coupling with the aniline analog according to the procedure of Louie et al. The coupled product is then N-protected, usually as a carbamate or amide, then the nitro group is reduced to the amine by catalytic hydrogenation or with tin(II) chloride in aqueous or alcohol solvent. A Z--A--B group in which Z-- incorporates a carbonyl functionality can then be used as a partner in a reductive alkylation with the primary amine function under the conditions described previously. This intermediate can then be submitted to the chemistry described in Scheme I, Route B to obtain a compound of Formula II. Route B describes the coupling of a protected phenethyl alcohol triflate with an amine containing Z--A--B group under the conditions recommended by Wolfe and Buchwald. This product is then N-protected as a suitable carbamate or amide and then processed by the chemistry described in Route B of Scheme I.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration fo the invention and are not intended to be limiting thereof.

EXAMPLES

The synthesis of representative compounds according to the invention is described in further detail below with reference to the following specific, but non-limiting examples.

Abbreviations used in the Examples are defined as follows: "°C" for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "DAST" for diethylaminosulfur trifluoride, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hr" for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "TLC" for thin layer chromatography.

Example 1 Preparation of N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea

4-(2-Hydroxyethyl)amino-1-benzylpiperidine

A mixture of 4-amino-1-benzylplperidine (1.0 g, 5.3mmol, 1.1 mL) and bromoethanol (0.662 g, 5.3 mmol, 0.375 mL) was stirred under a N₂ atmosphere for 18 h at ambient temperature. This material was used in directly in the next step (1.82 g). LRMS (M+H)⁺ m/z 235.

N-(3-Cyanophenyl)-N'-(2-hydroxyethyl)-N'-(1-benzylpiperidin-4-yl)urea

To a stirred solution of 4-(2-hydroxyethyl)amino-1-benzylpiperidine (1.82 g), and triethylamine (0.789 g, 7.8 mmol) in DMF (50 mL) was added 3-cyanophenylisocyanate (1.12 g, 7.8 mmol). This mixture was heated at 60° C. for 18 under a N₂ atmosphere. The reaction was diluted with water and extracted with ethyl acetate, dried with MgSO₄, filtered and concentrated to give the desired product, N-(3-cyanophenyl)-N'-(2-hydroxyethyl)-N'-(1-benzylpiperidin-4-yl)urea (2.04 g, 5.3 mmol). LRMS (M+H)⁺ m/z 379.

N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea

To a stirred solution of N-(3-cyanophenyl)-N'-(2-hydroxyethyl)-N'-(1-benzylpiperidin-4-yl)urea (2.04 g, 5.3 mmol) in chloroform at -10° C. was added a few drops of pyridine followed by thionyl chloride (0.702 g, 5.9 mmol). This mixture was stirred for 2 h then heated at reflux for 1 h. It was concentrated in vacuo, dissolved in ethanol (50 ml) and a solution of potassium hydroxide (10 %) in ethanol (15 mL) was added and refluxed for 2 h. The mixture was cooled then evaporated; it was dissoved in ethyl acetate, washed with water and brine then dried (MgSO₄). After removal of the solvent, the residue was purified by silica gel chromatography using ethyl acetate as the eluant. There was obtained 0.59 g of N-(3-cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea. LRMS (M+H)⁺ m/z 361.

N-(3-Amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea

A stirred solution of N-(3-cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea (56 mg) in anhydrous methanol (10 ml) was cooled to 0° C. and saturated with dry hydrogen chloride gas. This mixture was tightly stoppered and stirred at ambient temperature for 18 h. The solution was evaporated to dryness and the residual hydrogen chloride gas removed by pumping on the imidate salt for 18 h. The imidate was dissolved in anhydrous methanol (10 ml) and ammonium acetate (100 mg) was added. The mixture was stirred at ambient temperature for 24 h, then evaporated to give 55 mg of crude product. Purification of this material by reverse phase HPLC gave 26 mg of N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea as the bis-trifluoroacetic acid salt; HRMS Calc. 378.229386, found 378.229774; ¹ H NMR (CD₃ OD) d: 2.05-2.21 (m, 4H), 3.18 (dd, 2H, J=11 Hz, J=6.0 Hz), 3.58 (dd, 4H, J=11 Hz, J=6.0 Hz), 3.98 (t, 2H, J=7.5 Hz), 4.02 (m,1H), 4.32 (s, 1H), 7.45 (m, 7H), 7.81 (d,1H, J=7.5 Hz), 8.01 (s,1H).

Example 2 Preparation of N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cyclohexylurea

4-(3-Hydroxypropyl)amino-1-benzylpiperidine

This material was prepared in the same fashion as its lower homolog 4-(2-hydroxyethyl)amino-1-benzylpiperidine using 3-bromopropanol rather than 2-bromoethanol.

N-(3-Amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cyclohexylurea

This material was prepared from 4-(3-hydroxypropyl)amino-1-benzylpiperidine by the same route employed in the synthesis of N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea. There was obtained 26 mg of the desired product as the bis-tifluoroacetic acid salt after purification by reverse phase HPLC. LRMS (M+2H)²⁺ m/z 196.7, (M+H)⁺ m/z 392;¹ H NMR (CD₃ OD): d 2.23 (m, 6H), 3.21 (bt, 2H), 3.58 (t, 2H, J=5.12 Hz), 3.62 (m, 2H), 4.39 (m, 3H), 4.53 (t, 2H, J=5.12 Hz), 7.51 (m, 5H), 7.62-7.78 (m, 3H), 7.81 (s, 1H).

Example 3 Preparation of N-(3-amidinophenyl)-N'-(4-amidinophenyl)cycloheptylurea

N-(3-cyanophenyl)-N'-(4-cyanophenyl)urea

m-Cyanoaniline (0.5 g, 3.38 mmol) and p-cyanophenylisocyanate (0.49 g, 3.38 mmol) were dissolved in dimethylformaide (8 ml) and triethylamine (1 ml). The reaction was stirred at ambient temperature under a nitrogen atmosphere for 24 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water (3×), brine, dried (MgSO₄) and concentrated to give a amorphous solid. This was triturated to a crystalline white solid with ethyl ether. This solid was filtered and washed with ether to give N-(3-cyanophenyl)-N'-(4-cyanophenyl)urea as a white powder (0.92 g, mp 183-5° C.); LRMS (M+H)⁺ m/z 280, (M+NH₄)⁺ m/z 297; ¹ H NMR (DMSO-d₆): 9.32(s, 1H), 9.21(s, 1H), 7.97(s, 1H), 7.75-7.6(m, 5H), 7.55-7.4(m, 2H).

N-(3-cyanophenyl)-N'-(4-cyanophenyl)cycloheptylurea

N-(3-Cyanophenyl)-N'-(4-cyanophenyl)urea (0.25 g, 0.95 mmol) was dissolved in DMF (2 ml) and added to a cooled slurry of sodium hydride (0.80 g, 2.0 mmol, hexane washed to remove the mineral oil) in dimethylformamide (25 ml) under a nitrogen atmosphere. After strirring for 15 min, 1,4-dibromobutane (0.25 g, 0.95 mmol) was added slowly. The reaction was stirred at 0° C. for 1 h and then allowed to warm to 75° C. for 3 h. To the reaction additional sodium hydride was added and the reaction was heated to 75° C. for an additional 6 h. The reaction was allowed to cool to ambient temperature, was poured into 1N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO₄) and concentrated to give a viscous oil. The oil was purified by flash chromatography on silica gel eluting with methylene chloride: ethyl acetate 95:5 to give N-(3-cyanophenyl)-N'-(4-cyanophenyl)cycloheptylurea as an oil (0.075 gm 0.24 mmol); LRMS (M+H)⁺ m/z 317; ¹ H NMR (CDCl₃): 7.7-7.45(m, 6H), 7.4(d, 2H), 3.82(m, 4H), 1.95(m, 4H).

N-(3-amidinophenyl)-N'-(4-amidinophenyl)cycloheptylurea

Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N'-(4-cyanophenyl)cycloheptylurea (0.065 g, 0.21 mmol) in anhydrous ethanol (5 ml) under a nitrogen atmosphere for 15 min. The reaction was stoppered and allowed to warm to ambient temperature and stir overnight. The reaction was concentrated in vacuo to give a white amorphous solid. This was dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.118 g, 1.23 mmol) was added. The reaction was stirred under a nitrogen atmosphere at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give a white solid. The product was purified by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 20 minutes. The major fraction was concentrated to give N-(3-amidinophenyl)-N'-(4-amidinophenyl)cycloheptylurea as a white solid (mp204-206° C.); LRMS (M+H)⁺ m/z 351, (M+2H)⁺² m/z 176.2; HRMS calc. 351.1933, found 351.1936; ¹ H NMR (DMSO-d₆): 9.4(bs, 2H), 9.2(broad s, 2H), 9.18 (broad s, 2H), 7.95 (broad s, 2H), 7.8-7.5(m, 6H), 7.47 (d, 2H), 3.9(bd, 4H), 1.83(m, 4H).

Example 4 Preparation of N-(3-amidinophenyl)-N'-((4-amidinophenyl)methyl)cycloheptylurea

N-(3-cyanophenyl)-N'-((4-cyanophenyl)methyl)urea

m-Cyanophenyl isocyanate (2.0 g, 13.9 mmol) and triethylamine (3.09 g, 30.5 mmol) in dimethylformamide (30 ml) was cooled to 0° C. and p-cyanobenzylamine hydrogen chloride (2.3 g, 13.9 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction was thawed to ambient temperature and was stirred for 18 h. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with 1N HCl and brine, then dried (Na₂ SO₄) and evaporated. The crude product was purified by flash chromatography on silica gel with 1:1 hexane:ethyl acetate as an eluent; there was obtained 0.54 g of pure N-(3-cyanophenyl)-N'-((4-cyanophenyl)methyl)urea; LRMS (M+H)⁺ m/z 294.

N-(3-cyanophenyl)-N'-((4-cyanophenyl)methyl)cycloheptylurea

To a suspension of sodium hydride (0.29 g of a 60 % suspension in mineral oil, 7.28 mmol) in dimethylformamide (45 ml) at ambient temperature was added a dimethylformamide solution (5 ml) of N-(3-cyanophenyl)-N'-((4-cyanophenyl)methyl)urea (0.67 g, 2.43 mmol). This mixture was stirred for 30 min before 1,4-dibromobutane (1.05 g, 4.85 mmol) in dimethylformamide (10 ml) was added over 20 min. The reaction was then heated at 70° C. for 1 h, after which analysis by thin layer chromatography (1:2 hexane:ethyl acetate) demonstrated that all of the starting urea had been consumed. The cooled reaction mixture was poured into ice water and extracted with ethyl acetate (3×). The extract was washed with 1N HCl and brine, then dried (Na₂ SO₄) and evaporated. The crude product was purified by flash chromatography on a column of silica gel with 1:1 hexane:ethyl acetate as the eluent. There was obtained 0.47 g of pure N-(3-cyanophenyl)-N'-((4-cyanophenyl)methyl)cycloheptyl-urea; LRMS: (M+H)⁺ m/z 331.

N-(3-amidinophenyl)-N'-((4-amidinophenyl)methyl)cycloheptylurea

N-(3-Cyanophenyl)-N'-((4-cyanophenyl)methyl)cycloheptylurea (0.47 g, 1.42 mmol) was dissolved in a mixture of anhydrous chlorform (25 ml) and anhydrous methanol (10 ml). This solution was cooled to 0° C. and slowly saturated with dry hydrogen chloride gas. The reaction vessel was securely stoppered and stored in a refrigerator for 18 h; the solvent was removed in vacuo and there was obtained 0.59 g of the imidate as the hydrogen chloride salt; LRMS: (M+H)⁺ m/z 396.

The imidate prepared above (0.59 g) was stirred in anhydrous methanol (25 ml) with ammonium carbonate (0.72 g, 7.49 mmol). After 72 h the solvent was removed in vacuo and the residue dissolved in water. The aqueous solution was washed with ethyl ether (3×), then the water removed by lyophillization. The product was purified by HPLC on a Vydec® C-18 column eluting with solvent mixture A (water:TFA 99.5:0.5) and solvent mixture B (acetonitrile:TFA 99.5:0.5) using a gradient starting with A at 100% and changing to B at 100% over 50 min. The fractions containing pure N-(3-amidinophenyl)-N'-((4-amidinophenyl)methyl)cycloheptylurea were collected and lyophillized to give 0.027 g of material; HRMS (M+H)⁺ calc. 365.208985, found 365.209496.

Example 5 Preparation of N-(3-amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea

N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)urea

m-Cyanophenyl isocyanate (1.0 g, 6.94 mmol) was dissolved in dimethylformamide (15 ml) and triethylamine (2 ml) under a nitrogen atmosphere, then 4-amino-1-benzyl-piperidine (1.32 g, 6.94 mmol) was added slowly. The reaction was stirred at ambient temperature for 1 h and then at 70° C. for 2h. The reaction was allowed to cool to ambient temperature and partioned between water and ethyl acetate. The organic layer was washed with water (2×) and brine then dried (MgSO₄) and concentrated to give a white amorphous solid. The solid was triturated with ethyl ether to give a white powder. The solids was filtered, washed with ethyl ether and dried to give N-(3-cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea as a white powder, (1.7 g, 74%, mp 165-6° C.); LRMS (M+H)⁺ m/z 335; ¹ H NMR (CDCl₃): 7.62(s, 1H), 7.57(d, 1H), 7.15-7.2(M, 7H), 7.15(s, 1H), 5.05(d, 1H), 3.65(m, 1H), 3.5(s, 2H), 2.85(m,2H), 2.1(m,2H), 1.95(m, 2H), 1.45(m,2H).

N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea

N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)urea (0.5 g, 1.49 mmol) was dissolved in DMF (25 ml) and 1,4 dibromobutane (0.33 g, 1.49 mmol) was added under a nitrogen atmosphere. The reaction was heated to 70° C. and sodium hydride (0.131 gm 3.3 mmol) was added portionwise over 20 minutes. The reaction was heated for 4 h then allowed to cool to ambient temperature. When cool, it was poured into water and extracted with ethyl acetate. The organic layer was washed water (2×) and brine, then dried (MgSO₄) and concentrated to give a viscous oil. The crude oil was purified by flash chromatography on silica gel eluting with methylene chloride:ethyl acetate 40:60 to give N-(3-cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea as an oil (0.37 g, 64%); LRMS (M+H)⁺ m/z 389.4; ¹ H NMR (CDCl₃): 7.4-7.25(m, 9H), 3.9(m, 1H), 3.57(m, 2H), 3.42(s, 2H), 3.25(m, 2H), 2.87(m, 2H), 2.03(m, 2H), 1.8-1.5(m, 8H).

N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea

N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea (0.1 g 0.26 mmol) was dissolved in ethanol (10 ml) and cyclohexene (2 ml). Palladium hydroxide catalyst (0.05 g) was added and the reaction was heated at reflux under a nitrogen atmosphere. After 30 min the reaction was allowed to cool to ambient temperature, filtered and concentrated to give a viscous oil. The crude product was purified by flash chromatography on silica gel by eluting with methylene chloride:methanol 85:15 with 3% triethylamine. The product, N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea, was concentrated to give an oil which crystallized from ethyl ether (0.05 g, 48%, mp 157-8° C.); LRMS (M+H)⁺ m/z 299; ¹ H NMR (CDCl₃): 7.5-7.3(m, 4H), 4.05(m, 1H), 3.60(m, 2H), 3.32(m, 2H), 3.17(m, 2H), 2.72(m, 2H), 2.0-1.6(m, 8H).

N-(3-Cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea

N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (0.05 g, 0.126 mmol) was dissolved in pyridine (2 ml) and 3,5-dimethylpyrazole-1-carboxamidine (0.037 g, 0.188 mmol) was added under a nitrogen atmosphere. The reaction was heated to 110° C. for 6 h, then was allowed to cool and was concentrated to give a viscous amber oil. The product was purfied by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The product eluted at 13.8 minutes was concentrated to give N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea as an amorphous solid (0.036 g); LRMS (M+H)⁺ m/z 341.

N-(3-Amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea

Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cyclo-heptylurea (0.03 g, 0.075 mmol) in anhydrous ethanol (5 ml) for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to give a viscous residue which was dissolved in anhydrous ethanol and ammonium carbonate (0.06 g, 0.63 mmol) was added. The reaction was stirred over night at ambient temperature and then concentrated in vacuo. The crude product appeared to be about 1:2 ratio of the desired product to starting material. Pure N-(3-amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea was isolated by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 20 min, to give two major fractions: N-(3-amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea, the desired product eluted at 13.3 minutes, (8.2 mg); LRMS (M+2H)⁺² m/z 179.8; HRMS calc. 358.2355, found 358.2349; ¹ H NMR (DMSO-d₆): 9.25(s, 2H), 9.0(s, 2H), 7.55-7.4(m, 4H), 7.32(s, 4H), 3.95(m, 3H), 3.65(m, 2H), 3.25(m, 2H), 3.07(m, 2H), 1.8-1.6(m, 8H).

The second fraction, eluting at 18.1 min., was the starting material N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea (16.6 mg); LRMS (M+H)⁺ m/z 341.1; HRMS calc. 341.20898, found 3341.2077; ¹ H NMR (DMSO-d₆): 7.6(s, 1H), 7.5-7.4(m, 3H), 7.3(s, 4H), 4.0-3.9(m, 3H), 3.6(m, 2H), 3.25(m, 2H), 3.05(m, 2H), 1.8-1.55(m, 8H).

Example 6 Preparation of N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea

N-(3-Amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea

Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea (0.03 g, 0.077 mmol) in anhydrous ethanol (10 ml) under a nitrogen atmosphere for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to a solid and dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.023 g, 0.23 mmol) was added. The reaction mixture was stirred at ambient temperature overnight then was concentrated in vacuo. N-(3-Amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea was purified by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The major fraction eluting at 15 minutes was concentrated to give N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea as an amorphous solid; LRMS (M+H)⁺ m/z 406, (M+2H)⁺² m/z 203.8; ¹ H NMR (DMSO-d₆): 9.52(broad s, 1H), 9.27(s, 2H), 9.02(s, 2H), 7.5(m, 9H), 4.3(m,m, 2H), 3.95(m, 1H), 3.67(m, 2H), 3.42(m, 2H), 3.2(m, 2H), 3.1(m, 2H), 2.05-1.6(m, 8H).

Example 7 Preparation of N-(3-amidinophenyl)-N'-(1-(α-phenethyl)piperidin-4-yl)cycloheptylure

N-(3-amidinophenyl)-N'-(1-(a-phenethyl)piperidin-4-yl)cycloheptylurea

N-(3-amidinophenyl)-N'-(1-(a-phenethyl)piperidin-4-yl)cycloheptylurea was prepared by a method analogous to the preparation of N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea starting with 4-amino-1-(a-phenethyl)piperidine rather than 4-amino-1-benzylpiperidine; HRMS: calc 420.276336, found 420.276129; ¹ H NMR (CD₃ OD) d: 1.78 (d, 3H, J=6.95 Hz), 1.79 (m, 4H), 2.05 (m, 4H), 2.89 (m,3H), 3.38 (m, 2H), 3.76 (m,2H), 3.82 (broad d,2H), 3.92 (m,1H)4.42 (q, 1H, J=6.95 Hz), 7.42 (broad s,5H), 7.52 (broad s, 3H), 7.60 (s, 1H).

Example 8 Preparation of N-(3-amidinophenyl)-N'-(1-((phenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea

N-(3-Cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)urea

A mixture of 4-amino-N-(t-butoxycarbonyl)piperidine (0.133 mol, 30.5 g, prepared by the method of Mach, R. H. et al., J. Med. Chem. (1993) 36(23), 3707-20) and triethylamine (1.5 equivilents, 0.2 mol, 20.2 g, 27.8 ml) in dimethylformamide (230 ml) was cooled to 0° C. and m-cyanophenylisocyanate (1.1 equivilents, 0.146 mmol, 21.1 g) in dimethylformamide (70 ml) was added dropwise. The reaction was stirred at ambient temperature for 18 h. It was poured into water and extracted with ethyl acetate (3×). The ethyl acetate extracts were washed with 1N HCl and brine, then dried (Na₂ SO₄) and evaporated to give 43.56 g of crude material. Pure N-(3-cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)urea was isolated by flash chromatography on silica gel (1.2 kg) eluted with 2:1 hexane:ethyl acetate (6 L) then 1:1 heaxane ethyl acetate collected in 800 ml fractions. Fractions 9 thru 14 contained pure product, yield 21.69 g.

N-(3-Cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)cycloheptylurea

A mixture of sodium hydride (2.44 g of a 60% suspension in mineral oil, 60.9 mmol) and dimethylformamide (350 ml) was stirred at ambient temperature for 5 min, then N-(3-cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)urea (7.0 g, 20.3 mmol) in dimethylformamide (30 ml) was added dropwise. This mixture was stirred at ambient temperature for 30 min after which gas evolution ceased. 1,4-Dibromobutane (8.79 g, 40.6 mmol) in dimethylformamide (20 ml) was added slowly over 25 min. Following the addition of the alkylating agent the reaction mixture was heated at 70°-80° C. for 3 h then was stirred at ambient temperature for 18 h. The reaction mixture was poured into water (1 L) and extracted with ethyl acetate (4×250 ml). The ethyl acetate extracts were washed with brine (6×), dried (Na₂ SO₄) and evaporated to give 10.58 g of crude product. Pure N-(3-cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)cycloheptylurea was isolated by medium pressure chromatography on a silica gel column (600 g) by eluting with 2:1 hexane:ethyl acetate to give 3.20 g of pure product.

N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea

N-(3-Cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)cycloheptylurea (3.2 g, 7.76 mmol) was stirred in dichloromethane (40 ml) and trifluoroacetic acid (40 ml) at ambient temperature for 1.5 h. The reaction mixture was evaporated and the residue taken up in water. The aqueous suspension was made basic (pH 11) by the dropwise addition of aqueous sodium hydroxide solution (50%). The basic aqueous suspension was extracted with ethyl acetate (2×); the ethyl acetate extracts were washed with brine, dried (Na₂ SO₄), and evaporated to give N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (2.17 g, 7.28 mmol, 94%). This sample was in all respects identical to the sample of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea prepared in Example 5.

N-(3-Cyanophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea

N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (2.07 g, 6.95 mmol) in tetrahydrofuran (100 ml) with triethylamine (7.64 mmol, 0.77 g, 1.1 ml) was cooled to 0° C. and a-toluenesulfonyl chloride (1.46 g, 7.64 mmol) in tetrahydrofuran (60 ml) was added dropwise. The reaction was allowed to cool to ambient temperature and was stirred for 18 h. The solvent was removed in vacuo and the residue patitioned between water and 5:1 ethyl acetate:acetone. The organic layer was washed with 1N HCl and 1N NaOH, then brine. It was dried (Na₂ SO₄) and evaporated to give 2.63 g of crude product. Purification by medium pressure liquid chromatography on a silica gel column (350 g) gave N-(3-cyanophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea (1.81 g, 4.0 mmol, 58%, mp 203-204° C.); HRMS (M+H)⁺ calc. 453.196038, found 453.198085.

N-(3-amidinophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea

A solution of N-(3-cyanophenyl)-N'-(1-((phenyl)methane)-sulfonyl)piperidin-4-yl)cycloheptylurea (1.15 g, 2.54 mmol) in anhydrous methyl acetate (300 ml) was cooled to 0° C. and anhydrous methanol (0.81 g, 25.4 mmol, 1.02 ml) was added. The cooled solution was saturated with dry hydrogen chloride gas then was stoppered tightly and was left to stir at ambient temperature for 18 h. Analytical thin layer chromatography (5% methanol in chloroform) showed complete consumption of the starting nitrile. The methyl acetate solution was diluted with ethyl ether (1.7 L) then left to form crystals in the refrigerator over 18 h. After this time, precipitation of the imidate was complete and the intermediate product was isolated as the hydrogen chloride salt by filtration. The solid imidate was pumped on for several hours to remove any residual HCl and protect the product from moisture. This procedure gave 1.27 g of imidate hydrochloride (2.43 mmol, 96%, mp 131-134° C.).

The imidate prepared above (1.27 g, 2.43 mmol) was dissolved in dry methanol (50 ml) and 2N ammonia in methanol solution (24.3 mmol, 12.15 ml) was added. This reaction was stoppered and stirred at ambient temperature for 24 h. After this time, the solvent was removed in vacuo and the 1.27 g of crude product was isolated. The major contaminant (aproximately 50%) was the corresponding amide. This mixture was separated by HPLC on a Vydec® C-18 column eluting with solvent mixture A (water:TFA 99.5:0.5) and solvent mixture B (acetonitrile:TFA 99.5:0.5) using a gradient starting with A at 100% and changing to B at 100% over 50 min. The desired product, N-(3-amidinophenyl)-N'-(1-((phenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea, was eluted at 30 min; after collection of the fractions and lyophylization, 0.30 g of pure product was obtained as the trifluoroacetic acid salt (0.5 mmol, 20%, mp 208-209° C.); HRMS (M+H)⁺ calc. 470.222587, found 470.219813.

The following Example 9 to 12 were prepared by essentially the same preparative methods as described above for Example 8; the only changes involved the sulfonylation or acylation of the common intermediate N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea. In each case, however, the same procedure using the appropriate sulfonylating or acylating agent in tetrahydrofuran with triethylamine was used.

Example 9 Preparation of N-(3-amidinophenyl)-N'-(1-benzoylpiperidin-4-yl)cycloheptylurea

N-(3-amidinophenyl)-N'-(1-benzoylpiperidin-4-yl)cycloheptylurea

In this case the title compound was prepared by acylation of N-(3-cyanophenyl)-N'-(piperidin-4-In this case the title compound was prepared by acylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with benzoyl chloride followed by amidine formation as described above; HRMS (M+H)⁺ calc. 421.223966, found 421.222804.

Example 10 Preparation of N-(3-amidinophenyl)-N'-(1-((phenylmethane)carbonylpiperidin-4-yl)cycloheptylurea

N-(3-amidinophenyl)-N'-(1-((phenyl)methane)carbonylpiperidin-4-yl)cycloheptylurea

In this case the title compound was prepared by acylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with phenylacetyl chloride followed by amidine formation as described above; HRMS (M+H)⁺ calc. 434.255601, found 434.255065.

Example 11 Preparation of N-(3-amidinophenyl)-N'-(1-(phenyl)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-amidinophenyl)-N'-(1-(phenyl)sulfonylpiperidin-4-yl)cycloheptylurea

In this case the title compound was prepared by acylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with benzoyl chloride followed by amidine formation as described above; HRMS (M+H)⁺ calc. 456.206937, found 456.204189.

Example 12 Preparation of N-(3-amidinophenyl)-N'-(1-(4-acetamidophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-amidinophenyl)-N'-(1-(4-acetamidophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

In this case the title compound was prepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with (4-acetamidophenyl)sulfonyl chloride followed by amidine formation as described above; HRMS (M+H)⁺ calc. 513.228401, found 513.226577.

Example 13 Preparation of N-(3-amidinophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-cyanophenyl)-N'-(1-(2-nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (1.5 g, 5.03 mmol) in tetrahydrofuran (30 ml) and triethylamine (1.02 g, 10.06 mmol) was cooled to 0° C.

A solution of (2-nitrophenyl)sulfonyl chloride (1.3 g, 5.86 mmol) in tetrahydrofuran (5 ml) was added dropwise and the reaction was stirred at ambient temperature for 18 h. The solvent was removed in vacuo and the residue dissolved in ehtylacetate. The ethyl acetate solution was washed with 1N HCl and brine, then dried (Na₂ SO₄) and evaporated. Pure N-(3-cyanophenyl)-N'-(1-(2-nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea was isolated by flash chromatography on silica gel by first eluting with 2:1 hexane ehtyl acetate, then 1:1 hexane ethyl acetate. There was obtained 0.71 g of the title compound; LRMS (M+H)⁺ m/z 484.

N-(3-cyanophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl) cycloheptylurea

N-(3-cyanophenyl)-N'-(1-(2-nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea (0.71 g, 1.47 mmol) in ethanol (90 ml) and water (10 ml) was stirred with zinc dust (3.2 g, 48.6 mmol) and calcium chloride (0.11 g, 0.95 mmol). This mixture was heated at reflux for 3 h then filtered hot through a Celite® pad and evaporated; 0.59 g of N-(3-cyanophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea was obtained; LRMS (M+H)⁺ m/z 454.

N-(3-amidinophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-cyanophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea (0.20 g, 0.44 mmol) in anhydrous chloroform (25 ml) and anhydrous methanol (10 ml) was cooled to 0° C. and saturated with dry hydrogen chloride gas. The reaction vessel was securely stoppered and was stirred at ambient temperature for 18 h. The intermediate imidate was obtained as the hydrogen chloride salt (0.23 g) by removal of the solvent and residual hydrogen chloride in vacuo; LRMS (M+H)⁺ m/z 486.

The imidate prepared above (0.23 g) and a 2N solution of ammonia in methanol (1.5 ml) were stirred in a tightly stopper flask at ambient temperature for 18 h. A mixture of the desired amidine and the corresponding amide were obtained anfter removal of the solvent. This mixture was separated by HPLC on a Vydec® C-18 column eluting with solvent mixture A (water:TFA 99.5:0.5) and solvent mixture B (acetonitrile:TFA 99.5:0.5) using a gradient starting with A at 100% and changing to B at 100% over 50 min. There was obtained 38 mg of the desired product N-(3-amidinophenyl)-N'-(1-(2-aminophenyl)sulfonyl-piperidin-4-yl)cycloheptylurea; HRMS (M+H)⁺ calc. 471.217836, found 471.218097.

The corresponding amide side product N-(3-amidophenyl)-N'-(1-(2-aminophenyl)sulfonyl-piperidin-4-yl)cycloheptylurea was also isolated (46 mg); HRMS (M+H)⁺ calc. 472.201852, found 472.202530.

The following Example 14 to 16 were prepared by essentially the same preparative methods as described above for Example 13; the only changes involved the sulfonylation of the common intermediate N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea. In each case, however, the same procedure using the appropriate sulfonylating agent in tetrahydrofuran with triethylamine was used.

Example 14 Preparation of N-(3-amidinophenyl)-N'-(1-(3-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-amidinophenyl)-N'-(1-(3-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

In this case the title compound was prepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with 3-nitrophenylsulfonyl chloride. This product was reduced by a mixture of zinc dust and calcium chloride in aqueous ethanol followed by amidine formation as described above to give the title compound; HRMS (M+H)⁺ calc. 471.217836, found 471.219532.

Example 15 Preparation of N-(3-amidinophenyl)-N'-(1-(4-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-amidinophenyl)-N'-(1-(4-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea

In this case the title compound was prepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with 4-nitrophenylsulfonyl chloride.

This product was reduced by a mixture of zinc dust and calcium chloride in aqueous ethanol followed by amidine formation as described above to give the title compound; HRMS (M+H)⁺ calc. 471.217836, found 471.217059.

Example 16 Preparation of N-(3-amidinophenyl)-N'-(1-((2-aminophenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea

N-(3-amidinophenyl)-N'-(1-((2-aminophenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea

In this case the title compound was prepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with ((2-nitrophenyl)methane)sulfonyl chloride. This product was reduced by a mixture of zinc dust and calcium chloride in aqueous ethanol followed by amidine formation as described above to give the title compound; HRMS (M+H)⁺ calc. 485.233486, found 485.235037.

Example 17 Preparation of N-(3-amidinophenyl)-N'-(1-((2-acetamidophenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-cyanophenyl)-N'-(1-((2-aminophenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea

This material was prepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with ((2-nitrophenyl)methane)sulfonyl chloride in tetrahydrofuran and triethyl amine, as described for EXAMPLE 16. Reduction of the nitro group using zinc dust and calcium chloride in aqueous ethanol gave N-(3-cyanophenyl)-N'-(1-((2-aminophenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea; LRMS (M+H)⁺ m/z 468.

N-(3-cyanophenyl)-N'-(1-((2-acetamidophenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-cyanophenyl)-N'-(1-((2-aminophenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea (0.296 g, 0.63 mmol) in chloroform (30 ml) and triethylamine (0.13 g, 1.27 mmol) was cooled to 0° C. and acetyl chloride (0.06 g, 0.76 mmol) was added. The reaction was allowed to warm to ambient temperature and was stirred for 6 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with 1N HCl and brine, then dried (Na₂ SO₄) and evaporated. Purification by silica gel flash chromatography with 5% methanol in chloroform gave 194 mg of N-(3-cyanophenyl)-N'-(1-((2-acetamidophenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea; LRMS (M+H)⁺ m/z 510.

N-(3-amidinophenyl)-N'-(1-((2-acetamidophenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea

N-(3-cyanophenyl)-N'-(1-((2-acetamidophenyl)methane)sulfonyl-piperidin-4-yl)cycloheptylurea (0.194 g, 0.38 mmol) in anhydrous methyl acetate (25 ml) and anhydrous methanol (10 ml) was cooled to 0° C. and saturated with dry hydrogen chloride gas. The reaction vessel was securely stoppered and was stirred at ambient temperature for 18 h. The intermediate imidate was obtained as the hydrogen chloride salt (0.174 g) by removal of the solvent and residual hydrogen chloride in vacuo; LRMS (M+H)⁺ m/z 542.

The imidate prepared above (0.174 g) and a solution of ammonium acetate (0.15 g) in methanol (10 ml) were stirred at ambient temperature for 18 h. A mixture of the desired amidine and the corresponding amide were obtained after removal of the solvent. This mixture was separated by HPLC on a Vydec® C-18 column eluting with solvent mixture A (water:TFA 99.5:0.5) and solvent mixture B (acetonitrile:TFA 99.5:0.5) using a gradient starting with A at 100% and changing to B at 100% over 50 min. There was obtained 9.6 mg of the desired product N-(3-amidinophenyl)-N'-(1-((2-acetamidophenyl)methane)-sulfonylpiperidin-4-yl)cycloheptylurea; HRMS (M+H)⁺ calc. 527.244051, found 527.246420.

The corresponding amide side product N-(3-amidophenyl)-N'-(1-((2-acetamidophenyl)methane)-sulfonylpiperidin-4-yl)cycloheptylurea was also isolated (8.5 mg); HRMS (M+H)⁺ calc. 528.228066, found 528.236184.

Example 18 Preparation of 1-(1-benzoylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone

1-(1-t-butoxycarbonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone

A mixture of N-(3-cyanophenyl)-N'-(1-(t-butoxycarbonyl)-piperidin-4-yl)urea (0.50 g, 1.45 mmol) and sodium hydride (0.20 g of a 60% suspension in mineral oil, 8.3 mmol) in dimethylformamide was stirred at ambient temperature for 30 min. then cis-1,4-dichloro-2-butene (0.18 g, 1.44 mmol) was added. This mixture was heated at 70° C. for 4 h, after which an addition 0.2 g of 60% sodium hydride and 0.04 g of cis-1,4-dichloro-2-butene was added. The mixture was heated at 70° C. for an addition 2 h during which the remaining starting material was consumed. The reaction was diluted with brine (50 ml) and extracted with ethyl acetate (3×). The ethyl acetate extracts were washed with brine, then dried (Na₂ SO₄) and evaporated. The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexane:ethyl acetate to give 0.20 g of 1-(1-t-butoxycarbonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone; LRMS (M+H)⁺ m/z 397.

1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone

1-(1-t-Butoxycarbonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone (1.32 g, 3.3 mmol) was stirred in 1:1 dichloromethane:trifluoroacetic acid (30 ml) for 4 h. This solvent was removed in vacuo, and 1.35 g of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone was obtained as the trifluoroacetic acid salt LRMS (M+H)⁺ m/z 297.

1-(1-benzoylpiperidin-4-yl)-3-(3-cyanophenyl)-5-ethenyl-2-imidazolidinone

The free base of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone (1.99 g, 6.72 mmol) in tetrahydrofuran (50 ml) and triethylamine (1.36 g, 13,44 mmol) was cooled to 0° C. and benzoyl chloride in tetrahydrofuran (10 ml) was added. After 4 h the reaction was complete; the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N HCl and brine, then dried (Na₂ SO₄) and evaporated. The desired product was isolated by flash chromatography using silica get and 2:1 ethyl acetate as eluent. There was obtained 0.63 g of pure 1-(1-benzoylpiperidin-4-yl)-3-(3-cyanophenyl)-5-ethenyl-2-imidazolidinone; LRMS (M+H)⁺ m/z 401.

1-(1-benzoylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone

1-(1-Benzoylpiperidin-4-yl)-3-(3-cyanophenyl)-5-ethenyl-2-imidazolidinone (0.30 g, 0.75 mmol) in anhydrous 4:1 chloroform:methanol (25 ml) was cooled to 0° C. and saturated with dry hydrogen chloride gas. The reaction vessel was stoppered securely then left to stand at 10° C. for 72 h. The solvent was removed in vacuo to give 0.33 g of the imidate as the hydrogen chloride salt (0.75 mmol); LRMS (M+H)⁺ m/z 433.

The imidate prepared above (0.33 g, 0.75 mmol) was dissolved in anhydrous methanol (10 ml) and ammonium carbonate (0.36 g, 3.76 mmol) was added. This mixture was stirred at ambient temperature for 18 h, then the solvent was removed in vacuo. The residue was dissolved in water (10 ml) and washed with diethyl ether (3×). The aqueous layer was lyophillized and the crude product was purified by HPLC on a Vydec® C-18 column eluting with solvent mixture A (water:TFA 99.5:0.5) and solvent mixture B (acetonitrile:TFA 99.5:0.5) using a gradient starting with A at 100% and changing to B at 100% over 50 min. The fractions containing pure 1-(1-benzoylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone were collected and lyophillized to give 0.090 g of material; HRMS (M+H)⁺ calc. 418.224300, found 418.223792.

The following Example 19 and 20 were prepared by essentailly the same preparative methods as described above for Example 18; the only changes involved the sulfonylation of the common intermediate 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone. In each case, however, the same procedure using the appropriate acylating or sulfonylating agent in tetrahydrofuran with triethylamine was used.

Example 19 Preparation of 1-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone

In this case the title compound was prepared by sulfonylation of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone with α-toluene sulfonyl chloride in tetrahydrofuran with triethylamine followed by amidine formation as described above; HRMS (M+H)⁺ calc. 468.206937, found 468.204978.

Example 20 Preparation of 1-(1-phenylsulfonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone

In this case the title compound was prepared by sulfonylation of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone with phenylsulfonyl chloride in tetrahydrofuran with triethylamine followed by amidine formation as described above; HRMS (M+H)⁺ calc. 454.191287, found 454.191418.

Example 21 Preparation of 1,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one

N- methyl(2-((t-butyldimethylsilyloxy)methyl)phenyl)!-N- (N-carbo-t-butoxy)piperidin-4-yl!amine

A solution of methyl-2-cyanobenzoate (10 g, 62.11 mmol) in ethyl ether (300 mL) was added dropwise to a slurry of lithium aluminum hydride in ethyl ether (200 mL). After the addition was complete, more ether was added (200 mL) and the mixture heated at reflux for 2 h. The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), 1N sodium hydroxide solution (7.1 mL) and water (21.3 mL). The reaction was filtered and evaporated to give 6.96 g (50.8 mmol) of 2-(aminomethyl)benzyl alcohol. This material was carried on without further purification.

The material from above was dissolved in tetrahydrofuran (140 mL) and cooled to 0° C. To this mixture was added imidazole (1.3 equivilents, 4.5 g, 66.04 mmol) and t-butyldimethylsilyl chloride (1.05 equivilents, 8.04 g, 53.34 mmol). The reaction mixture was stirred at ambient temperature for 18 h then was diluted with water (500 mL) and extracted with ethyl ether (3×150 mL). The ether extract was dried (MgSO₄) and evaporated to give 10.78 g (41 mmol) of the t-butyldimethylsilyl ether of 2-(aminomethyl)benzyl alcohol.

To a mixture of the t-butyldimethylsilyl ether prepared above (7.77 g, 29.5 mmol) and N-(carbo-t-butoxy)piperidin-4-one (5.88 g, 29.5 mmol) in methanol at 0° C. was added zinc chloride (4.02 g, 29.5 mmol) followed by sodium cyanoborohydride (2.04 g, 32.45 mmol). The reaction was thawed to ambient temperature and stirred for 18 h. After this time, the reaction was judged to be complete by TLC (20% methanol in chloroform); the solvent was removed by distillation in vacuo and the residue partitioned between ethyl acetate and 1N hydrochloric acid solution. The ethyl acetate layer was washed with brine and dried (MgSO₄) then evaporated to give 11.66 g (26.87 mmol) of N- methyl(2-((t-butyldimethylsilyloxy)methyl)phenyl)!-N- (N'-carbo-t-butoxy)piperidin-4-yl!amine.

N- methyl(2-(chloromethyl)phenyl)!-N- (N'-carbo-t-butoxy)piperidin-4-yl!-(3-cyano)benzamide

A mixture of 11.66 g (26.87 mmol) of N- methyl(2-((t-butyldimethylsilyloxy)-methyl)phenyl)!-N- (N-carbo-t-butoxy)piperidin-4-yl!amine and 3-cyanophenyl isocyanate (3.87 g, 26.87 mmol) in dimethyl-formamide (100 mL) was stirred at ambient temperature for 24 h. The reaction was judged to be complete by TLC (5% methanol in chloroform) and diluted with brine (500 mL). The suspension was extracted with ethyl acetate (150 mL) and the ethyl acetate extracts were washed with brine (5×100 mL) then dried (MgSO₄) and evaporated to give 14.54 g of crude material. This material was purified further by elution from a 400 gram column of silica gel with a mixture of ethyl acetate and hexane; the material isolated from the eluent was 11.66 g (20.17 mmol) of the pure isocyanate addition product.

A tetrahydrofuran solution (200 mL) of the purified isocyanate addition product (11.5 g, 20 mmol) was treated with solid tetra-n-butylammonium fluoride (5.75 g, 22 mmol). The reaction was complete in 30 min (TLC, 1:1 hexane:ethyl acetate) whereupon the solvent was removed by distillation in vacuo and the residue partioned between ethyl acetae and water. The ethyl acetate layer was dried (MgSO₄) and evaporated to give 13.23 g of the desilylsted benzyl alcohol tainted with a silyl fluoro- or silyloxy-side product from the cleaved protecting group. This material was assumed to contain a quantitative yield of the desired benzyl alcohol (20 mmol) and dissolved in chloroform (300 mL). The cooled solution (0° C.) was treated with triethylamine (2.23 g, 3.1 mL, 22 mmol) followed by the dropwise addition of methanesulfonyl chloride (2.29 g, 1.55 mL, 20 mmol) in chloroform (50 mL). The reaction was allowed to thaw to ambient temperature and stirred for 18 h. The reaction was washed with 5% sodium hydrogensulfate solution (2×150 mL) then dried and evaporated to give 10.25 g of crude product as the benzyl chloride. A portion of this material (ca. 5 g) was purified further by elution from a 400 g column of silica gel with 3:1 hexane:ethyl acetate. The pure N- methyl(2-(chloromethyl)phenyl)!-N- (N'-carbo-t-butoxy)piperidin-4-yl!-(3-cyano)benzamide (3.1 g, 6.43 mmol) was isolated from the eluent as a white solid mp: 165-170° C.

1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one

The pure N- methyl(2-(chloromethyl)phenyl)!-N- (N'-carbo-t-butoxy)piperidin-4-yl!-(3-cyano)benzamide (3.1 g, 6.43 mmol) was dissolved in dimethylformamide (30 mL), cooled to 0° C. and a 60% suspension of sodium hydride in mineral oil (0.52 g of suspension, 12.46 mmol) was added. The reaction was complete after 2 h at 0° C.; it was diluted with water (150 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate solution was washed with brine (5×50 mL), then was dried and evaporated. The yield of the cyclized product was 2.7 g (6.05 mmol); this material was contaminated with a small amount of mineral oil but was carried on to the next step without further purification.

The t-butoxycarbonyl protecting group on the product prepared above (2.7 g, 6.05 mmol) was removed by treatment with 4N hydrogen chloride in dioxane (15 mL) at 0° C. for 3 h. The reaction mixture was purged with nitrogen gas, then evaporated. The residue was dissolved in water (50 mL) and washed with ethyl ether (2×25 mL). The water solution was made basic (pH 12) with 10% sodium hydroxide solution and the product extracted with ethyl acetate (3×50 mL). The ethyl acetate solution was washed with 1N aqueous sodium hydroxide, then was dried (MgSO₄) and evaporated to give 1.62 g (4.68 mmol) of 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one as a tan solid, mp 115.8° C.; HRMS for C₂₁ H₂₃ N₄ O (M+H)⁺ : calc. 347.187187, found 347.184824.

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one

A solution of 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one (0.805 g, 2.33 mmol) in tetrahydrofuran (50 mL) was cooled to 0° C. and triethylamine (0.26 g, 0.36 mL 2.6 mmol) was added. To this mixture a tetrahydrofuran solution (25 mL) of benzylsulfonyl chloride (0.5 g, 2.6 mmol) was added dropwise. The reaction mixture was allowed to thaw to ambient temperature and stirred for 24 h. TLC indicated that the reaction was complete (10% methanol in chloroform). The mixture was evaporated and the residue suspended in a 3:1 mixture of water:1N hydrogen chloride solution. The product solidified, the suspension was filtered and the resulting powder air-dried, to give 0.89 g of crude product. This material was purified further by flash chromatography with a column of silica gel (80 g) and eluting with 2:1 then 1:1 hexane:ethyl acetate. From the eluent there was isolated 0.41 g (0.82 mmol) of pure 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one, mp: 205-207° C.

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one

A solution of 0.41 g (0.82 mmol) of pure 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in chloroform (10 mL) was added to a saturated solution of dry, gaseous hydrogen chloride in dry methanol (10 mL) and chloroform (50 mL) at -78° C. The reaction vessel was stoppered tightly and allowed to thaw to ambient temperature; this mixture was maintained in this fashion for 18 h. After this time, excess hydrogen chloride gas was removed from the reaction mixture by purging with a stream of dry nitrogen gas; the solution was then evaporated and pumped on for several hours to remove traces of free hydrogen chloride gas. The resulting imidate was detected by LRMS:m/z (M+H)⁺ =533. This material was dissolved in a solution of dry chloroform (20 mL) and 2.0 M ammonia in methanol (5 mL, 10 mmol), the reaction vessel was stoppered tightly and stirred at ambient temperature for 6 days. The reaction mixture was evaporated and there was obtained about 0.45 g of the amidine product contaiminated with the amide side product. This mixture was purified by HPLC, eluting with a an aqueous phase of 0.05% trifluoroacetic acid in water and an organic phase of 0.05% trifluoroacetic acid in acetonitrile. The product, 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one (0.11 g, 0.17 mmol), was isolated as the trifluoroacetic acid salt by lyophylization of the appropriate fractions; mp: 210-211° C.; purity >99.5% (HPLC); HRMS: (M+H)⁺ for C₂₈ H₃₁ N₅ SO₃, calc. 518.222587, found 518.221085.

Example 22 Preparation of 1,2,4,5-tetrahydro-2-(thiopen-2-yl)sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one

The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one was sulfonylated with (thiophen-2-yl)sulfonyl chloride according to the procedure outlined for the preparation of 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

The title compound was obtained via the imidate according to the procedure for 1,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one of EXAMPLE 21 by starting with the intermediate prepared above. LRMS: m/z=509; mp=119-120° C.

Example 23 Preparation of 1,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one

The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one was prepared from methyl 3,4-dimethoxy-6-cyanobenzoate according to the procedure for the preparation of 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one was sulfonylated with benzylsulfonyl chloride according to the procedure outlined for the preparation of 1,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

The title compound was obtained via the imidate according to the procedure for 1,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one of EXAMPLE 21 by starting with the intermediate prepared above. HRMS: (M+H)⁺ for C₃₀ H₃₅ N₅ O₅ S, calc. 578.243716, found 578.245119.

Example 24 Preparation of 1,2,4,5-tetrahydro-2-(thiophen-2-yl)sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one

The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one was prepared from methyl 3,4-dimethoxy-6-cyanobenzoate according to the procedure for the preparation of 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one was sulfonylated with (thiophen-2-yl)sulfonyl chloride according to the procedure outlined for the preparation of 1,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

The title compound was obtained via the imidate according to the procedure for 1,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one of EXAMPLE 21 by starting with the intermediate prepared above. HRMS: (M+H)⁺ for C₂₇ H₃₁ N₅ O₅ S₂, calc. 570.184488, found 570.186900.

Examples 25 to 55 (Shown in Table 7)

Examples 25 to 55 were prepared by essentially the same preparative methods as described above for Example 8; the only changes involved the sulfonylation, alkylation or acylation of the common intermediate N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea. In each case, the same procedure using the appropriate sulfonyl chloride, sulfamoyl chloride, alkyl chloride or acyl chloride in tetrahydrofuran with triethylamine was used. Following imidate formation, the reaction with methanolic ammonia to give the amidine product was executed as described in Example 13.

An exceptional case was the preparation of Example 28; this product was obtained as a by-product of the formation of the amidine Example 29. During the methanolic ammonia step competing deacylation of Example 29 led to the formation of Example 28. Both Examples 28 and 29 were obtained pure and homogeneous by HPLC purification of the mixture obtained during amidine formation under standard preparative HPLC purification conditions.

Example 56 Preparation of N-(3-amidinophenyl)-N'-((1-((phenyl)-1,1-dimethyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea

The title compound was prepared from N-(3-cyanophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea found in Example 8

N-(3-cyanophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea (1.94 g, 4.29 mmol) in dimethylformamide (25 mL) was cooled to -10° C. and 1M potassium t-butoxide solution in tetrahydrofuran (12.9 mL, 12.9 mmol) was added dropwise. The reaction was stirred for 15 min at -10° C. then methyl iodide (1.83 g, 12.9 mmol) was added. After 2 h reaction was complete by TLC; the reaction micture was poured into water (200 mL), then was extracted with ethyl acetate (3×50 mL). The ethyl acetate extracts were washed with water (5×50 mL), dried (MgSO₄) and evaporated to give 0.55 g of N-(3-cyanophenyl)-N'-((1-((phenyl)-1,1-dimethyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea; LRMS (M+NH₄)⁺ m/z=498.

To 0.55 g of N-(3-cyanophenyl)-N'-((1-((phenyl)-1,1-dimethyl)methane)-sulfonyl)-piperidin-4-yl)cycloheptylurea (1.14 mmol) in pyridine (20 mL) with triethylamine (1 mL) was passed a stream of gaseous hydrogen sulfide for 30 min. The reaction mixture was stoppered tightly and allowed to stand for 18 h. The solution was then poured into 1N hydrochloric acid solution (250 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate solution was dried and evaportated to give 0.53 g (1.03 mmol) of N-(3-thioamidophenyl)-N'-((1-((phenyl)-1,1-dimethyl)methane)-sulfonyl)-piperidin-4-yl)cycloheptylurea; LRMS (M+H)⁺ m/z=515.

The product prepared above, 0.53 g (1.03 mmol) of N-(3-thioamidophenyl)-N'-(1-((phenyl)-1,1-dimethyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea, was stirred in methyl iodide (10 mL) for 2 h. The reaction was then evaporated to give 0.62 g (1.03 mmol) of the thioimidate.

The thioimidate (o.62 g, 1.03 mmol) was stirred with ammonium acetate (0.45 g, 5.9 mmol) in methanol (20 mL) and heated at 60° C. for 2 h. The reaction was then evaporated, the residue stirred in dichloromethane, the insoluable material removed by filtration and the dichloromethane solution evaporated to give ca. 0.5 g of crude amidine. This material was purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.143 g of the title compound following lyophylization of the appropriate fractions; HRMS (M+H)⁺ calc. 489.253887, found 498.252412.

Example 57 Preparation of N-(3-amidinophenyl)-N'-(methyl((phenylmethane)carbamide)morpholin-3-yl))cycloheptylurea

N-benzyl 3-(aminomethyl)morpholine

N-benzyl 3-(chloromethyl)morpholine (10 g, 44.3 mmol) in dimethylformamide (200 mL) with sodium azide (8.64 g, 133 mmol) and potassium iodide (0.73 g) was heated at 100° C. for 72 h. The reaction was poured into water (1 L) and extracted with ethyl acetate (3×150 mL). The ethyl acetate layer was washed with water (5×150 mL), then dried (MgSO₄) and evaporated to give 9.28 g of material. This was purified further by flash chromatography using 3:1 hexane:ethyl acetate as the eluent. There was obtained 7.89 g of the pure azide.

The material prepared above was dissolved in methanol (300 mL) and palladium hydroxide catalyst (1.0 g) was added. This mixture was stirred under an atmosphere of hydrogen gas at ambient pressure for 2 h, whereupon selective reduction of the azide group was complete. The reaction mixture was purged with nitrogen gas and the catalyst removed by filtration through a Celite pad.After removal of the solvent there was obtained 5.80 g of N-benzyl 3-(aminomethyl)morpholine (28.1 mmol); LRMS (M+H)⁺ m/z=207.

N-(3-cyanophenyl)-N'-(methyl(N-methyl(phenyl))morpholin-3-yl))cycloheptylurea

A mixture of 5.80 g of N-benzyl 3-(aminomethyl)morpholine (28.1 mmol) and 3-cyanophenyl isocyanate (4.46 g, 31 mmol) in dimethylformamide (100 mL) was stirred at ambient temperature for 18 h. The reaction was diluted with water (500 mL) then extracted with ethyl acetate (3×100 mL). The ethyl acetate solution was washed with water (5×100 mL), dried (MgSO₄) and evaporated to give 9.49 g of the urea (27.1 mmol); LRMS (M+H)⁺ m/z=351.

To a mixture of sodium hydride (3.25 g of a 60% suspension in mineral oil, 81.3 mmol) in dimethylformamide (450 mL) was added dropwise 9.49 g of the urea (27.1 mmol) prepared above as a solution in dimethylformamide (50 mL). This mixture was stirred for 30 min, then 1,71 g of 1,4-dibromobutane (54.2 mmol) in dimethylformamide (40 mL) was added slowly. The reaction was heated to 70° C. for 6 h then poured into water (2 L) and extracted with ethyl acetate (3×250 mL). The ethyl acetate extract was washed with water (5×250 mL), was dried (MgSO₄) and evaporated. The residue was purified by flash chromatography using 2:1 hexane:ethyl acetate as an eluent. There was obtained 7.59 g of N-(3-cyanophenyl)-N'-(methyl(N-methyl(phenyl))morpholin-3-yl))cycloheptylurea; LRMS (M+H)⁺ m/z=405.

N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea

To N-(3-cyanophenyl)-N'-(methyl(N-methyl(phenyl))morpholin-3-yl))cycloheptylurea (4.66 g, 11.55 mmol) in dichloromethane (100 mL) was added 1-chloroethyl chloroformate (1.81 g, 12.7 mmol) in dichloromethane (10 mL). After 2 h the reaction was complete by TLC; the solvent was removed by evaporation in vaccuo and replaced by methanol (60 mL). The mixture was refluxed for 1 h then the solvent evaporated to give 3.53 g of N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea; LRMS (M+H)⁺ m/z=315.

N-(3-cyanophenyl)-N'-(methyl((phenylmethane)carbamide)morpholin-3-yl))cycloheptylurea

To 1.0 g of N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea (3.18 mmol) in tetrahydrofuran (30 mL) with triethylamine (0.68 g, 6.7 mmol) at 0° C. was added phenylacetyl chloride (0.54 g, 3.5 mmol) in tetrahydrofuran (10 mL). The mixture was allowed to thaw to ambient temperature and stirred for 18 h. After this time, the solvent was removed by evaporation in vacuo and the residue purified by flash chromatography with 10% methanol in chloroform used as the eluent. There was obtained 1.17 g (2.7 mmol) of N-(3-cyanophenyl)-N'-(methyl((phenyl-methane)carbamide)morpholin-3-yl))cycloheptylurea as product; LRMS (M+H)⁺ m/z=433.

N-(3-amidinophenyl)-N'-(methyl((phenyl-methane)carbamide)morpholin-3-yl))cycloheptylurea

To a saturated solution of gaseous hydrogen chloride in dry chloroform (20 mL) and dry methanol (8 mL) at -78° C. was added dropwise a chloroform (5 mL) solution of 1.17 g (2.7 mmol) of N-(3-cyanophenyl)-N'-(methyl((phenyl-methane)carbamide)morpholin-3-yl))cycloheptylurea. This mixture was stoppered tightly, was allowed to thaw to ambient temperature and was stirred for 18 h. The solvent was removed in vacuo to give 1.04 g of the corresponding imidate; LRMS (M+H)⁺ m/z=465.

The imidate prepared above was dissolved in 2M ammonia in methanol solution (6.72 mmol, 3.36 mL), the flask was stoppered securely and the mixture stirred at ambient temperature for 18 h. After this time the solvent was removed in vacuo and the residue (ca. 1.2 g) was purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.12 g of N-(3-amidinophenyl)-N'-(methyl((phenyl-methane)carbamide)-morpholin-3-yl))cycloheptylurea; mp 49-53° C.; HRMS (M+H)⁺ : calc. 450.250515, found 450.251817.

Example 58 Preparation of N-(3-amidinophenyl)-N'-(methyl((thiophen-2-yl)sulfonyl)morpholin-3-yl)cycloheptylurea

This compound was prepared by the same methods used for Example 57. Starting with the common intermediate N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea, this material was sulfonylated with (thiophen-2-yl)sulfonyl chloride using the same conditions for the acylation described above. There was obtained 0.75 g of the sulfonylation product following purification by flash chromatography using a gradient of 2:1 hexane:ethyl acetate to 1:2 hexane:ethyl acetate as a gradient; LRMS (M+H)⁺ m/z=461.

The imidate and subsequently, the amidine N-(3-amidinophenyl)-N'-(methyl((thiophen-2-yl)sulfonyl)morpholin-3-yl))cycloheptylurea were obtained as described. Following HPLC purification 0.32 g of the title compound was isolated; mp 78-83° C.; HRMS (M+H)⁺ : calc. 478.158273, found 478.156983.

Example 59 Preparation of N-(3-amidinophenyl)-N'-(methyl((phenylmethane)sulfonyl)morpholin-3-yl))cycloheptylurea

This compound was prepared by the same methods used for Example 57. Starting with the common intermediate N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea, this material was sulfonylated with (phenyl)methylsulfonyl chloride using the same conditions for the acylation described above. There was obtained 0.68 g of the sulfonylation product following purification by flash chromatography using a gradient of 1:1 hexane:ethyl acetate to 1:3 hexane:ethyl acetate as a gradient; LRMS (M+H)⁺ m/z=469.

The imidate and subsequently, the amidine N-(3-amidinophenyl)-N'-(methyl((phenylmethane)sulfonyl)morpholin-3-yl))cycloheptylurea were obtained as described above. Following HPLC purification 0.102 g of the title compound was isolated; mp 45-53° C.; HRMS (M+H)⁺ : calc. 486.217502, found 486.217928.

Example 60 Preparation of N-(3-amidinophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylurea

N-Benzyl 3-aminopiperidine

To 10.0 g of N-benzyl 3-hydroxypiperidine hydrogen chloride salt (44 mmol) in chloroform (200 mL) with triethylamine (9.34 g, 92.4 mmol) at 0° C. was added dropwise methanesulfonyl chloride (5.54 g, 48.4 mmol) in chloroform (10 mL). The reaction mixture was allowed to thaw to ambient temperature and stirred 72 h. After this time, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (200 mL) and washed with water (200 mL). The organic solution was dried (MgSO₄) and evaporated to give 9.1 g (33.8 mmol) of the mesitylate.

The material prepared above was dissolved in dimethylformamide (200 mL) and stirred at 100° C. with sodium azide (11 g, 170 mmol). After 48 h the reaction was complete by TLC; it was diluted with brine (200 mL) and extracted with ethyl acetate (3×100 mL). The ethyl acetate extracts were washed with water (5×100 mL), then dried and evaporated to give 6.12 g of the azide; LRMS (M+H)⁺ m/z=217.

The azide (6.12 g, 28.4 mmol) in methanol (250 mL) with palladium hydroxide catalyst (1.0 g) was stirred under an atmosphere of hydrogen gas at ambient pressure for 1 h 15 min. After this time selective reduction of the azide was complete. The reaction mixture was purged with nitrogen gas and the catalyst removed by filtration through a Celite pad. The solvent was removed by distillation in vacuo to give 4.3 g of N-benzyl 3-aminopiperidine; LRMS (M+H)⁺ m/z=191.

N-(3-cyanophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylurea

A mixture of 4.3 g of N-benzyl 3-aminopiperidine (22.6 mmol) and 3-cyanophenyl isocyanate (3.58 g, 24.9 mmol) in dimethylformamide (100 mL) was stirred at ambient temperature for 18 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (3×150 mL). The organic solution was washed with water (5×100 mL), dried and evaporated. This material was purified further by flash chromatography on silica gel using a gradient of 1:1 to 3:1 ethyl acetate:hexane. There was obtained 3.18 g of the pure urea (9.52 mmol); LRMS (M+H)⁺ m/z=335.

To 1.14 g of sodium hydride (60% suspension, 28.6 mmol) in dimethylformamide (160 mL) was added a dimethylformamide (20 mL) solution of the urea (3.18 g, 9.52 mmol). After 30 min. 1,4-dibromobutane (4.32 g, 20 mmol) in dimethylformamide (10 mL) was added dropwise, then the mixture was heated to 70° C. for 3 h. The reaction was diluted with water (700 mL) and extracted with ethyl acetate (3×100 mL). The organic solution was washed with water (5×100 mL), dried (MgSO₄) and evaporated. The residue was purified by flash chromatography on silica gel using an elution gradient of 5 to 10% methanol in chloroform. There was obtaine 3.17 g of N-(3-cyanophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylurea; LRMS (M+H)⁺ m/z=389.

N-(3-amidinophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylurea

To a saturated solution of hydrogen chloride gas in dry methanol (8 mL) and dry chloroform (15 mL) at -78° C. was added a chloroform (5 mL) solution of N-(3-cyanophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptyl-urea (0.5 g, 1.29 mmol). The reaction mixture was stoppered securely and allowed to stir at ambient temperature for 18 h. After this time the solvent was removed in vacuo and 0.49 g of the imidate hydrochloride salt was obtained; LRMS (M+H)⁺ m/z=422.

The imidate obtained above was dissolved in 2M ammonia in methanol (1.75 mL, 3.5 mmol). The reaction vessel was stoppered securely and the mixture stirred at ambient temperature for 18 h. After this time the solvent was removed in vacuo and the residue was purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.015 g of pure N-(3-amidinophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylurea; HRMS (M+H)⁺ : calc.406.260686, found 406.259064.

Example 61 Preparation of N-(3-amidinophenyl)-N'-((N-(benzyl)sulfonyl)piperidin-3-yl)cycloheptylurea

N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea

A mixture of N-(3-cyanophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptyl-urea (prepared in Example 60, 2.7 g, 6.98 mmol) and α-chloroethyl chloroformate (1.09 g, 7.65 mmol) was stirred at ambient temperature for 2.5 h, whereupon the reaction was complete as judged by TLC. The solvent was removed by evaporation in vacuo and was replaced with methanol (40 mL). The reaction was heated at reflux until all of the newly formed intermediate was consumed as indicated by TLC. Evaporation of the solvent gave 2.49 g of N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea; LRMS (M+H)⁺ m/z=299.

N-(3-cyanophenyl)-N'-((N-(benzyl)sulfonyl)piperidin-3-yl)cycloheptylurea

To N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea (1.2 g, 4.03 mmol) and triethylamine (0.85 g, 8.46 mmol) in tetrahydrofuran (30 mL) at 0° C. was added benzylsulfonyl chloride (0.92 g, 4.83 mmol) in tetrahydrofuran solution (10 mL). The reaction was allowed to thaw to ambient temperature then stirred for 18 h. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (100 mL). The organic solution was washed with 1N sodium hydroxide solution (100 mL), 1N hydrochloric acid (100 mL) and saturated sodium hydrogen carbonate (100 mL). The solution was dried (MgSO₄) and evaporated to give 0.99 g (2.19 mmol) of N-(3-cyanophenyl)-N'-((N-(benzyl)sulfonyl)piperidin-3-yl)cycloheptylurea; LRMS (M+H)⁺ m/z=453.

N-(3-amidinophenyl)-N'-((N-(benzyl)sulfonyl)piperidin-3-yl)cycloheptylurea

To a -78° C. saturated solution of hydrogen chloride gas in dry chloroform (20 mL) and methanol(10 mL) was added 0.99 g (2.19 mmol) of N-(3-cyanophenyl)-N'-((N-(benzyl)-sulfonyl)piperidin-3-yl)cycloheptylurea in chloroform (5 mL). The reaction vessel was stoppered securely, was allowed to thaw to ambient temperature and was stirred 18 h. After this time the solvent was removed by evaporation in vacuo and there was obtained 1.04 g of the imidate as the hydrogen chloride salt; LRMS (M+H)⁺ m/z=485.

The imidate prepared above was dissolved in 2M ammonia in methanol solution (3.22 mL, 6.44 mmol). The reaction was stoppered securely and was stirred for 18 h. Following removal of the solvent and purification by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) there was obtained 0.316 g of N-(3-amidinophenyl)-N'-((N-(benzyl)sulfonyl)piperidin-3-yl)cycloheptylurea; HRMS (M+H)⁺ : calc.470.225587, found 470.221857.

Additionally, there was isolated as a slower eluting peak 0.066 g of the amide side product, N-(3-amidophenyl)-N'-((N-(benzyl)sulfonyl)piperidin-3-yl)cycloheptylurea.

Example 62 Preparation of N-(3-amidinophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylurea

This compound was prepared by the same methods used for Example 61. Starting with the common intermediate N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea, this material was sulfonylated with (thiophen-2-yl)sulfonyl chloride using the same conditions for the sulfonylation described above. There was obtained 0.87 g of the sulfonylation product following purification by flash chromatography using a gradient of 2:1 hexane:ethyl acetate to 1:1 hexane:ethyl acetate as a gradient; LRMS (M+H)⁺ m/z=445.

The imidate and subsequently, the amidine N-(3-amidinophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylurea were obtained as described above. Following HPLC purification 0.234 g of the title compound was isolated; HRMS (M+H)⁺ : calc. 462.163359, found 462.164841.

Additionally, there was isolated as a slower eluting peak 0.045 g of the amide side product, N-(3-amidophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylurea; HRMS (M+H)⁺ : calc. 463.147374, found 463.146300.

Example 63 Preparation of N-(3-amidinophenyl)-N'-(4-(2-sulfonamidophenyl)phenyl)cycloheptylurea

N-(3-cyanophenyl)-N'-(4-bromophenyl)cycloheptylurea

A mixture of 3-cyanophenyl isocyanate (3.76 g, 26.1 mmol) and 4-bromoaniline (4.5 g, 26.1 mmol) in 1:1 tetrahydrofuran:chloroform (100 mL). After 72 h at ambient temperature, product was isolated by filtration, the filtrate was washed with cold chloroform and air dried to give 6.6 g of N-(3-cyanophenyl)-N'-(4-bromophenyl)urea (21 mmol).

To 1.41 g of sodium hydride (60% suspension, 33.6 mmol) in dimethylformamide (300 mL) was added a dimethylformamide (20 mL) solution of 6.6 g of N-(3-cyanophenyl)-N'-(4-bromophenyl)urea (21 mmol). After 30 min, 1,4-dibromobutane (6.2 g, 28.6 mmol) in dimethylformamide (10 mL) was added dropwise, then the mixture was heated to 60° C. for 2 h and then was stirred at ambient temperature for 18 h. The reaction was diluted with water (700 mL) and extracted with ethyl acetate (3×100 mL). The organic solution was washed with water (5×100 mL), dried (MgSO₄) and evaporated. The residue was purified by flash chromatography on silica gel using an elution gradient of 5 to 10% methanol in chloroform. There was obtained 3.68 g of N-(3-cyanophenyl)-N'-(4-bromophenyl)cycloheptylurea.

N-(3-cyanophenyl)-N'-(4-(2-((N-t-butyl)sulfonamido)phenyl)phenyl)cycloheptylurea

A mixture of N-(3-cyanophenyl)-N'-(4-bromophenyl)cycloheptylurea (4.0 g, 10.81 mmol), 2-((N-t-butyl)sulfonamido)phenylboronic acid (3.9 g, 15.2 mmol), tetrabutylammonium bromide (0.203 g) and sodium carbonate (2.47 g) in benzene (170 mL) was thoroughly purged with dry nitrogen gas. Tetrakis(triphenylphosphine)palladium(0) catalyst (0.635 g) was added and the mixture was heated at reflux under a nitrogen atmosphere for 18 h. The benzene solution was washed with water (3×100 mL) and brine (100 mL), then dried (MgSO₄) and evaporated. The crude product was triturated with n-butylchloride, filtered and air dried to give 3.92 g of N-(3-cyanophenyl)-N'-(4-(2-((N-t-butyl)sulfon-amido)phenyl)-phenyl)cycloheptylurea.

N-(3-amidinophenyl)-N'-(4-(2-sulfonamidophenyl)phenyl)cycloheptylurea

A solution of 3.0 g of N-(3-cyanophenyl)-N'-(4-(2-((N-t-butyl)sulfon-amido)phenyl)phenyl)cycloheptylurea (5.98 mmol) in dry methanol (40 mL) and dry chloroform (300 mL) was saturated with hydrogen chloride gas with ice cooling. This solution was stoppered tightly and was stirred for 18 h at ambient temperature. The solvent was removed by evaporation and the residue dissolved in 2M ammonia in methanol (60 mmol, 30 mL). This solution was stirred in a securely stoppered reaction vessel for 48 h at ambient temperature. After this time the solvent was removed in vacuo and 2.28 g of crude product was obtained. A portion (0.735 g) of this material was purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.396 g of pure N-(3-amidinophenyl)-N'-(4-(2-sulfonamidophenyl)phenyl)cycloheptylurea; mp 163-166° C. HRMS (M+H)⁺ : calc.464.175637, found 464.177525.

Example 64 Preparation of N-(3-amidinophenyl)-N'-(5-(2-sulfonamidophenyl)pyridin-2-yl)cycloheptylurea

Example 64 was prepared by a procedure similar to that used for Example 63 with the exception that 2-amino-5-bromopyridine was substituted for 4-bromoaniline in the intial step. There was obtained 0.043 g of N-(3-amidinophenyl)-N'-(5-(2-sulfonamido-phenyl)pyridin-2-yl)cycloheptylurea as a bis trifluoroacetate salt; mp 75-79° C.; HRMS (M+H)⁺ : calc. 465.170886, found 465.170759.

Example 65 Preparation of N-(3-amidinophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea

N-(3-cyanophenyl)-N'-(methyl(4-bromo)phenyl)urea

A mixture of 4-bromobenzyl amine (3.81 g, 20 mmol) and 3-cyanophenyl isocyanate (2.65 g, 18.4 mmol) in dimethylformamide (60 mL) was stirred at ambient temperature for 48 h. The reaction was partioned between 1N hydrochloric acid solution (200 mL) and ethyl acetate (200 mL). The ethyl acetate solution was washed with water (5×100 mL), then dried (MgSO₄) and evaporated to give 5.33 g of N-(3-cyanophenyl)-N'-(methyl(4-bromo)phenyl)urea.

N-(3-cyanophenyl)-N'-(methyl(4-bromophenyl))cycloheptylurea

To 1.82 g of sodium hydride (60% suspension, 45.3 mmol) in dimethylformamide (270 mL) was added a dimethylformamide (30 mL) solution of the N-(3-cyanophenyl)-N'-(methyl(4-bromo)phenyl)urea (4.98 g g, 15.1 mmol). After 30 min, 1,4-dibromobutane (6.52 g, 30.2 mmol) in dimethylformamide (10 mL) was added dropwise. This mixture was heated to 70° C. for 3 h then cooled to ambient temperature and stirred for 48 h. The reaction was diluted with water (1 L) and extracted with ethyl acetate (4×250 mL). The organic solution was washed with water (5×150 mL), dried (MgSO₄) and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1% methanol in chloroform. There was obtained 2.3 g of N-(3-cyanophenyl)-N'-(methyl(4-bromophenyl))cycloheptylurea.

N-(3-cyanophenyl)-N'-(methyl(4-(2-(N-t-buty)sulfonamidophenyl)phenyl))cycloheptylurea

A mixture of N-(3-cyanophenyl)-N'-(methyl(4-bromophenyl))cycloheptylurea (1.24 g, 3.2 mmol), 2-((N-t-butyl)sulfonamido)phenylboronic acid (1.17 g, 4.5 mmol), tetrabutylammonium bromide (0.06 g) and sodium carbonate (0.73 g) in benzene (50 mL) and water (5 mL) was thoroughly purged with dry nitrogen gas. Tetrakis(tri-phenylphosphine)palladium(0) catalyst (0.188 g) was added and the mixture was heated at reflux under a nitrogen atmosphere for 18 h. The benzene solution was washed with water (3×100 mL) and brine (100 mL), then dried (MgSO₄) and evaporated to give 2.0 g of crude product. Recrystallization from acetone gave 0.80 g of N-(3-cyanophenyl)-N'-(methyl(4-(2-(N-t-buty)sulfonamido-phenyl)phenyl))cycloheptylurea; mp 177-179° C.

An additional 0.365 g of product was recovered from the mother liquors by silica gel chromatography using 1% methanol in chloroform as an eluent.

N-(3-cyanophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea

A solution of 1.17 g of N-(3-cyano-phenyl)-N'-(methyl(4-(2-(N-t-buty)sulfonamidophenyl)phenyl))cycloheptylurea (2.27 mmol) in trifluoroacetic acid (30 mL) was heated at reflux for 1 h. The reaction was evaporated and the residue suspended in 10% sodium hydroxide solution (30 mL). The suspension was extracted with ethyl acetate (50 mL), the extracts were washed with 10% sodium hydroxide solution (2×25 mL) and brine (25 mL). The solution was dried (MgSO₄) and evaporated to give 0.72 g of crude product. This material was purified by column chromatography using a gradient of 1.5 to 2.5% methanol in chloroform. There was obtained 0.55 g of N-(3-cyanophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea.

N-(3-amidinophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea

A solution of 0.55 g of N-(3-cyanophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea (1.2 mmol) in dry methyl acetate (70 mL) and dry methanol (0.192 g, 0.24 mL, 6.0 mmol) was cooled to 0° C. and saturated with dry hydrogen chloride gas. The reaction was stoppered tightly and stirred at ambient temperature 18 h. Precipitation of the imidate product was initiated by the addition of ethyl ether (70 mL) to the cold solution. The solid was isolated by filtration and maintained in vacuo for 18 h to remove the last traces of hydrogen chloride gas; there was obtained 0.50 g of the imidate as the hydrogen chloride salt.

The imidate from above was stirred for 18 h in a methanol (20 mL) solution of ammonium acetate (0.462 g, 6 mmol). The reaction was evaporated and partioned between ethyl acetate (50 mL) and 1N hydrochloric acid (50 mL). The ethyl acetate solution was dried and evaporated to give 0.16 g of the amide side-product. Lyophylization of the hydrochloric acid solution gave 0.39 g of the crude amidine. Purification of this material by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) gave 0.258 g of N-(3-amidinophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea as the trifluoroacetic acid salt; mp 90-94° C.; HRMS (M+H)⁺ calc. 478.191671, found 478.191287.

                  TABLE 5     ______________________________________     1 #STR25##                                            HRMS                                            (M + H).sup.+     Ex. n     R.sup.2    A       B         m/z     ______________________________________      1  0     H          4-piperidinyl                                  N-benzyl  378.229774      2  1     H          4-piperidinyl                                  N-benzyl  LRMS (M + H).sup.+ m/z 392      3  2     H          phenyl  4-amidino 351.1936      4  2     H          benzyl  4-amidino 365.209496      5  2     H          4-piperidinyl                                  N-(amidino)                                            358.2349      6  2     H          4-piperidinyl                                  N-benzyl  LRMS (M + H).sup.+ m/z 406      7  2     H          4-piperidinyl                                  N-(1-phenethyl))                                            420.276129      8  2     H          4-piperidinyl                                  N-benzylsulfonyl                                            470.219813      9  2     H          4-piperidinyl                                  N-benzoyl 421.222804     10  2     H          4-piperidinyl                                  N-benzylcarbonyl                                            434.255065     11  2     H          4-piperidinyl                                  N-phenylsulfonyl                                            456.204189     12  2     H          4-piperidinyl                                  N-(4-acetamido- phenylsulfonyl)                                            513.226577     13  2     H          4-piperidinyl                                  N-(2-amino- phenylsulfonyl)                                            471.218097     14  2     H          4-piperidinyl                                  N-(3-amino- phenylsulfonyl)                                            471.219532     15  2     H          4-piperidinyl                                  N-(4-amino- phenylsulfonyl)                                            471.217059     16  2     H          4-piperidinyl                                  N-(2-aminophenyl- methane-sulfonyl)                                            485.235037     17  2     H          4-piperidinyl                                  N-(2-acetamido- phenylmethane-                                            527.246420     18  0     --CH═CH.sub.2                          4-piperidinyl                                  N-phenylmethane- carbonyl                                            418.223792     19  0     --CH═CH.sub.2                          4-piperidinyl                                  N-benzylsulfonyl                                            468.204978     20  0     --CH═CH.sub.2                          4-piperidinyl                                  N-phenylsulfonyl                                            454.191418     ______________________________________

                  TABLE 6     ______________________________________     2 #STR26##     Ex.  R.sup.10   B             HRMS (M + H).sup.+  m/z     ______________________________________     21   H          benzylsulfonyl                                   518.221085     22   H          2-thiophenylsulfonyl                                   LRMS: m/z = 509     23   7,8-di-OCH.sub.3                     benzylsulfonyl                                   578.245119     24   7,8-di-OCH.sub.3                     2-thiophenylsulfonyl                                   570.186900     ______________________________________

                  TABLE 7     ______________________________________     3 #STR27##                                        HRMS                                        (M + H).sup.+     Ex. Z-A        B*                  m/z     ______________________________________     25  4-piperidinyl                    2-fluorophenylsulfonyl                                        474.198031     26  4-piperidinyl                    isopropylsulfonyl   422.222957     27  4-piperidinyl                    8-quinolinylsulfonyl                                        507.217649     28  4-piperidinyl                    1-(5-amino-4-methylthiazolyl)- sulfonyl                                        492.183742     29  4-piperidinyl                    1-(5-N-acetylamino-4-methylthiazol- yl)sulfonyl                                        534.193475     30  4-piperidinyl                    4 #STR28##          514.168829     31  4-piperidinyl                    2-(5-chlorothiophenyl)                                        497.124056     32  4-piperidinyl                    3-(2-carbomethoxy)thiophenyl- sulfonyl                                        520.168929     33  4-piperidinyl                    2-thiophenylsulfonyl                                        462.163248     34  4-piperidinyl                    2-carbomethoxyphenylsulfonyl                                        514.212199     35  4-piperidinyl                    2-pyridylmethyl     407.258632     36  4-piperidinyl                    3-pyridylmethyl     407.255034     37  4-piperidinyl                    cyclohexylaminosulfonyl                                        477.2646     38  4-piperidinyl                    isopropylaminosulfonyl                                        437.2339     39  4-piperidinyl                    phenylaminosulfonyl 471.2182     40  4-piperidinyl                    phenylaminocarbonyl 435.2519     41  4-piperidinyl                    cyclohexylaminocarbonyl                                        441.2968     42  4-piperidinyl                    phenyl-N-methylaminosulfonyl                                        485.2340     43  4-piperidinyl                    4-pyridylmethyl     407.255561     44  4-piperidinyl                    3-pyridylmethylsulfonyl                                        471.218739     45  4-piperidinyl                    1-naphthylsulfonyl  506.222676     46  4-piperidinyl                    2-naphthylsulfonyl  506.221512     47  4-piperidinyl                    5-(2-phenylsulfonylthiophenyl)- sulfonyl                                        602.158636     48  4-piperidinyl                    3-pyridylsulfonyl   457.204869     49  4-piperidinyl                    2-(4-phenylsulfonylthiophenyl)- sulfonyl                                        602.157432     50  4-piperidinyl                    5-(N-methylimidazolyl)sulfonyl                                        460.213785     51  4-piperidinyl                    2-pyridylmethylsulfonyl                                        471.219270     52  4-piperidinyl                    2-thiophenylmethyl  412.216008     53  4-piperidinyl                    4-fluorophenylsulfonyl                                        474.199222     54  4-piperidinyl                    4-fluorophenylmethylsulfonyl                                        488.210708     53  4-piperidinyl                    3,5-bistrifluoromethylphenylsulfonyl                                        592.181914     54  4-piperidinyl                    2-trifluoromethylphenylsulfonyl                                        524.193512     55  4-piperidinyl                    2-pyridylsulfonyl   457.202166     56  4-piperidinyl                    (1,1-dimethyl-1-phenyl)methyl- sulfonyl                                        498.252412     57  3-morpholinyl- methyl                    N-(benzylcarbonyl)  450.251817     58  3-morpholinyl- methyl                    N-(thiophen-2-ylsulfonyl)                                        478.156983     59  3-morpholinyl- methyl                    N-(benzylsulfonyl)  486.217928     60  3-piperidinyl                    N-benzyl            406.259064     61  3-piperidinyl                    N-(benzylsulfonyl)  470.221857     62  3-piperidinyl                    N-(thiophenylsulfonyl)                                        462.164841     63  phenyl     2-sulfonamidophenyl 464.177525     64  2-pyridyl  2-sulfonamidophenyl 465.170759     65  benzyl     2-sulfonamidophenyl 478.191287     ______________________________________      *Unless otherwise indicated, group B is substituted on A para to Z, if      present, and the cyclourea.

                  TABLE 8     ______________________________________     5 #STR29##     Ex.  n     R.sup.2   Z    A.sup.1                                    A.sup.2                                         B     ______________________________________     101  0     H         bond CH   CH   amino     102  0     H         bond CH   CH   amidino     103  0     H         bond CH   CH   guanidino     104  0     H         bond CH   CH   2-sulfamidophenyl     105  0     H         bond CH   CH   2-trifluoromethylphenyl     106  0     OH        bond CH   CH   amino     107  0     OH        bond CH   CH   amidino     108  0     OH        bond CH   CH   guanidino     109  0     OH        bond CH   CH   2-sulfamidophenyl     110  0     OH        bond CH   CH   2-trifluoromethylphenyl     111  0     NHC(O)CH.sub.3                          bond CH   CH   amino     112  0     NHC(O)CH.sub.3                          bond CH   CH   amidino     113  0     NHC(O)CH.sub.3                          bond CH   CH   guanidino     114  0     NHC(O)CH.sub.3                          bond CH   CH   2-sulfamidophenyl     115  0     NHC(O)CH.sub.3                          bond CH   CH   2-trifluoromethylphenyl     116  0     NHSO.sub.2 CH.sub.3                          bond CH   CH   amino     117  0     NHSO.sub.2 CH.sub.3                          bond CH   CH   amidino     118  0     NHSO.sub.2 CH.sub.3                          bond CH   CH   guanidino     119  0     NHSO.sub.2 CH.sub.3                          bond CH   CH   2-sulfamidophenyl     120  0     NHSO.sub.2 CH.sub.3                          bond CH   CH   2-trifluoromethylphenyl     121  0     OCH.sub.3 bond CH   CH   amino     122  0     OCH.sub.3 bond CH   CH   amidino     123  0     OCH.sub.3 bond CH   CH   guanidino     124  0     OCH.sub.3 bond CH   CH   2-sulfamidophenyl     125  0     OCH.sub.3 bond CH   CH   2-trifluoromethylphenyl     126  0     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   amino     127  0     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   amidino     128  0     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   guanidino     129  0     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   2-sulfamidophenyl     130  0     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   2-trifluoromethylphenyl     131  0     H         CH.sub.2                               CH   CH   amino     132  0     H         CH.sub.2                               CH   CH   amidino     133  0     H         CH.sub.2                               CH   CH   guanidino     134  0     H         CH.sub.2                               CH   CH   2-sulfamidophenyl     135  0     H         CH.sub.2                               CH   CH   2-trifluoromethylphenyl     136  0     OH        CH.sub.2                               CH   CH   amino     137  0     OH        CH.sub.2                               CH   CH   amidino     138  0     OH        CH.sub.2                               CH   CH   guanidino     139  0     OH        CH.sub.2                               CH   CH   2-sulfamidophenyl     140  0     OH        CH.sub.2                               CH   CH   2-trifluoromethylphenyl     141  0     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   amino     142  0     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   amidino     143  0     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   guanidino     144  0     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   2-sulfamidophenyl     145  0     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     146  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   amino     147  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   amidino     148  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   guanidino     149  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   2-sulfamidophenyl     150  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     151  0     OCH.sub.3 CH.sub.2                               CH   CH   amino     152  0     OCH.sub.3 CH.sub.2                               CH   CH   amidino     153  0     OCH.sub.3 CH.sub.2                               CH   CH   guanidino     154  0     OCH.sub.3 CH.sub.2                               CH   CH   2-sulfamidophenyl     155  0     OCH.sub.3 CH.sub.2                               CH   CH   2-trifluoromethylphenyl     156  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   amino     157  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   amidino     158  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   guanidino     159  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   2-sulfamidophenyl     160  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     161  0     H         bond N    CH   amino     162  0     H         bond N    CH   amidino     163  0     H         bond N    CH   guanidino     164  0     H         bond N    CH   2-sulfamidophenyl     165  0     H         bond N    CH   2-trifluoromethylphenyl     166  0     OH        bond N    CH   amino     167  0     OH        bond N    CH   amidino     168  0     OH        bond N    CH   guanidino     169  0     OH        bond N    CH   2-sulfamidophenyl     170  0     OH        bond N    CH   2-trifluoromethylphenyl     171  0     NHC(O)CH.sub.3                          bond N    CH   amino     172  0     NHC(O)CH.sub.3                          bond N    CH   amidino     173  0     NHC(O)CH.sub.3                          bond N    CH   guanidino     174  0     NHC(O)CH.sub.3                          bond N    CH   2-sulfamidophenyl     175  0     NHC(O)CH.sub.3                          bond N    CH   2-trifluoromethylphenyl     176  0     NHSO.sub.2 CH.sub.3                          bond N    CH   amino     177  0     NHSO.sub.2 CH.sub.3                          bond N    CH   amidino     178  0     NHSO.sub.2 CH.sub.3                          bond N    CH   guanidino     179  0     NHSO.sub.2 CH.sub.3                          bond N    CH   2-sulfamidophenyl     180  0     NHSO.sub.2 CH.sub.3                          bond N    CH   2-trifluoromethylphenyl     181  0     OCH.sub.3 bond N    CH   amino     182  0     OCH.sub.3 bond N    CH   amidino     183  0     OCH.sub.3 bond N    CH   guanidino     184  0     OCH.sub.3 bond N    CH   2-sulfamidophenyl     185  0     OCH.sub.3 bond N    CH   2-trifluoromethylphenyl     186  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   amino     187  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   amidino     188  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   guanidino     189  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   2-sulfamidophenyl     190  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   2-trifluoromethylphenyl     191  0     H         CH.sub.2                               N    CH   amino     192  0     H         CH.sub.2                               N    CH   amidino     193  0     H         CH.sub.2                               N    CH   guanidino     194  0     H         CH.sub.2                               N    CH   2-sulfamidophenyl     195  0     H         CH.sub.2                               N    CH   2-trifluoromethylphenyl     196  0     OH        CH.sub.2                               N    CH   amino     197  0     OH        CH.sub.2                               N    CH   amidino     198  0     OH        CH.sub.2                               N    CH   guanidino     199  0     OH        CH.sub.2                               N    CH   2-sulfamidophenyl     200  0     OH        CH.sub.2                               N    CH   2-trifluoromethylphenyl     201  0     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   amino     202  0     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   amidino     203  0     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   guanidino     204  0     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   2-sulfamidophenyl     205  0     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     206  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   amino     207  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   amidino     208  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   guanidino     209  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   2-sulfamidophenyl     210  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     211  0     OCH.sub.3 CH.sub.2                               N    CH   amino     212  0     OCH.sub.3 CH.sub.2                               N    CH   amidino     213  0     OCH.sub.3 CH.sub.2                               N    CH   guanidino     214  0     OCH.sub.3 CH.sub.2                               N    CH   2-sulfamidophenyl     215  0     OCH.sub.3 CH.sub.2                               N    CH   2-trifluoromethylphenyl     216  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   amino     217  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   amidino     218  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   guanidino     219  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   2-sulflamidophenyl     220  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     221  0     H         bond N    N    amino     222  0     H         bond N    N    amidino     223  0     H         bond N    N    guanidino     224  0     H         bond N    N    2-sulfamidophenyl     225  0     H         bond N    N    2-trifluoromethylphenyl     226  0     OH        bond N    N    amino     227  0     OH        bond N    N    amidino     228  0     OH        bond N    N    guanidino     229  0     OH        bond N    N    2-sulfamidophenyl     230  0     OH        bond N    N    2-trifluoromethylphenyl     231  0     NHC(O)CH.sub.3                          bond N    N    amino     232  0     NHC(O)CH.sub.3                          bond N    N    amidino     233  0     NHC(O)CH.sub.3                          bond N    N    guanidino     234  0     NHC(O)CH.sub.3                          bond N    N    2-sulfamidophenyl     235  0     NHC(O)CH.sub.3                          bond N    N    2-trifluoromethylphenyl     236  0     NHSO.sub.2 CH.sub.3                          bond N    N    amino     237  0     NHSO.sub.2 CH.sub.3                          bond N    N    amidino     238  0     NHSO.sub.2 CH.sub.3                          bond N    N    guanidino     239  0     NHSO.sub.2 CH.sub.3                          bond N    N    2-sulfamidophenyl     240  0     NHSO.sub.2 CH.sub.3                          bond N    N    2-trifluoromethylphenyl     241  0     OCH.sub.3 bond N    N    amino     242  0     OCH.sub.3 bond N    N    amidino     243  0     OCH.sub.3 bond N    N    guanidino     244  0     OCH.sub.3 bond N    N    2-sulfamidophenyl     245  0     OCH.sub.3 bond N    N    2-trifluoromethylphenyl     246  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    amino     247  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    amidino     248  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    guanidino     249  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    2-sulfamidophenyl     250  0     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    2-trifluoromethylphenyl     251  0     H         CH.sub.2                               N    N    amino     252  0     H         CH.sub.2                               N    N    amidino     253  0     H         CH.sub.2                               N    N    guanidino     254  0     H         CH.sub.2                               N    N    2-sulfamidophenyl     255  0     H         CH.sub.2                               N    N    2-trifluoromethylphenyl     256  0     OH        CH.sub.2                               N    N    amino     257  0     OH        CH.sub.2                               N    N    amidino     258  0     OH        CH.sub.2                               N    N    guanidino     259  0     OH        CH.sub.2                               N    N    2-sulfamidophenyl     260  0     OH        CH.sub.2                               N    N    2-trifluoromethylphenyl     261  0     NHC(O)CH.sub.3                          CH.sub.2                               N    N    amino     262  0     NHC(O)CH.sub.3                          CH.sub.2                               N    N    amidino     263  0     NHC(O)CH.sub.3                          CH.sub.2                               N    N    guanidino     264  0     NHC(O)CH.sub.3                          CH.sub.2                               N    N    2-sulfamidophenyl     265  0     NHC(O)CH.sub.3                          CH.sub.2                               N    N    2-trifluoromethylphenyl     266  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    amino     267  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    amidino     268  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    guanidino     269  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    2-sulfamidophenyl     270  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    2-trifluoromethylphenyl     271  0     OCH.sub.3 CH.sub.2                               N    N    amino     272  0     OCH.sub.3 CH.sub.2                               N    N    amidino     273  0     OCH.sub.3 CH.sub.2                               N    N    guanidino     274  0     OCH.sub.3 CH.sub.2                               N    N    2-sulfamidophenyl     275  0     OCH.sub.3 CH.sub.2                               N    N    2-trifluoromethylphenyl     276  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    amino     277  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    amidino     278  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    guanidino     279  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    2-sulfamidophenyl     280  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    2-trifluoromethylphenyl     ______________________________________

                  TABLE 9     ______________________________________     6 #STR30##     Ex.  n     R.sup.2   Z    A.sup.1                                    A.sup.2                                         B     ______________________________________     301  1     H         bond CH   CH   amino     302  1     H         bond CH   CH   amidino     303  1     H         bond CH   CH   guanidino     304  1     H         bond CH   CH   2-sulfamidophenyl     305  1     H         bond CH   CH   2-trifluoromethylphenyl     306  1     OH        bond CH   CH   amino     307  1     OH        bond CH   CH   amidino     308  1     OH        bond CH   CH   guanidino     309  1     OH        bond CH   CH   2-sulfamidophenyl     310  1     OH        bond CH   CH   2-trifluoromethylphenyl     311  1     NHC(O)CH.sub.3                          bond CH   CH   amino     312  1     NHC(O)CH.sub.3                          bond CH   CH   amidino     313  1     NHC(O)CH.sub.3                          bond CH   CH   guanidino     314  1     NHC(O)CH.sub.3                          bond CH   CH   2-sulfamidophenyl     315  1     NHC(O)CH.sub.3                          bond CH   CH   2-trifluoromethylphenyl     316  1     NHSO.sub.2 CH.sub.3                          bond CH   CH   amino     317  1     NHSO.sub.2 CH.sub.3                          bond CH   CH   amidino     318  1     NHSO.sub.2 CH.sub.3                          bond CH   CH   guanidino     319  1     NHSO.sub.2 CH.sub.3                          bond CH   CH   2-sulfamidophenyl     320  1     NHSO.sub.2 CH.sub.3                          bond CH   CH   2-trifluoromethylphenyl     321  1     OCH.sub.3 bond CH   CH   amino     322  1     OCH.sub.3 bond CH   CH   amidino     323  1     OCH.sub.3 bond CH   CH   guanidino     324  1     OCH.sub.3 bond CH   CH   2-sulfamidophenyl     325  1     OCH.sub.3 bond CH   CH   2-trifluoromethylphenyl     326  1     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   amino     327  1     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   amidino     328  1     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   guanidino     329  1     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   2-sulfamidophenyl     330  1     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   2-trifluoromethylphenyl     331  1     H         CH.sub.2                               CH   CH   amino     332  1     H         CH.sub.2                               CH   CH   amidino     333  1     H         CH.sub.2                               CH   CH   guanidino     334  1     H         CH.sub.2                               CH   CH   2-sulfamidophenyl     335  1     H         CH.sub.2                               CH   CH   2-trifluoromethylphenyl     336  1     OH        CH.sub.2                               CH   CH   amino     337  1     OH        CH.sub.2                               CH   CH   amidino     338  1     OH        CH.sub.2                               CH   CH   guanidino     339  1     OH        CH.sub.2                               CH   CH   2-sulfamidophenyl     340  1     OH        CH.sub.2                               CH   CH   2-trifluoromethylphenyl     341  1     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   amino     342  1     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   amidino     343  1     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   guanidino     344  1     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   2-sulfamidophenyl     345  1     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     346  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   amino     347  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   amidino     348  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   guanidino     349  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   2-sulfamidophenyl     350  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     351  1     OCH.sub.3 CH.sub.2                               CH   CH   amino     352  1     OCH.sub.3 CH.sub.2                               CH   CH   amidino     353  1     OCH.sub.3 CH.sub.2                               CH   CH   guanidino     354  1     OCH.sub.3 CH.sub.2                               CH   CH   2-sulfamidophenyl     355  1     OCH.sub.3 CH.sub.2                               CH   CH   2-trifluoromethylphenyl     356  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   amino     357  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   amidino     358  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   guanidino     359  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   2-sulfamidophenyl     360  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     361  1     H         bond N    CH   amino     362  1     H         bond N    CH   amidino     363  1     H         bond N    CH   guanidino     364  1     H         bond N    CH   2-sulfamidophenyl     365  1     H         bond N    CH   2-trifluoromethylphenyl     366  1     OH        bond N    CH   amino     367  1     OH        bond N    CH   amidino     368  1     OH        bond N    CH   guanidino     369  1     OH        bond N    CH   2-sulfamidophenyl     370  1     OH        bond N    CH   2-trifluoromethylphenyl     371  1     NHC(O)CH.sub.3                          bond N    CH   amino     372  1     NHC(O)CH.sub.3                          bond N    CH   amidino     373  1     NHC(O)CH.sub.3                          bond N    CH   guanidino     374  1     NHC(O)CH.sub.3                          bond N    CH   2-sulfamidophenyl     375  1     NHC(O)CH.sub.3                          bond N    CH   2-trifluoromethylphenyl     376  1     NHSO.sub.2 CH.sub.3                          bond N    CH   amino     377  1     NHSO.sub.2 CH.sub.3                          bond N    CH   amidino     378  1     NHSO.sub.2 CH.sub.3                          bond N    CH   guanidino     379  1     NHSO.sub.2 CH.sub.3                          bond N    CH   2-sulfamidophenyl     380  1     NHSO.sub.2 CH.sub.3                          bond N    CH   2-trifluoromethylphenyl     381  1     OCH.sub.3 bond N    CH   amino     382  1     OCH.sub.3 bond N    CH   amidino     383  1     OCH.sub.3 bond N    CH   guanidino     384  1     OCH.sub.3 bond N    CH   2-sulfamidophenyl     385  1     OCH.sub.3 bond N    CH   2-trifluoromethylphenyl     386  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   amino     387  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   amidino     388  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   guanidino     389  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   2-sulfamidophenyl     390  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   2-trifluoromethylphenyl     391  1     H         CH.sub.2                               N    CH   amino     392  1     H         CH.sub.2                               N    CH   amidino     393  1     H         CH.sub.2                               N    CH   guanidino     394  1     H         CH.sub.2                               N    CH   2-sulfamidophenyl     395  1     H         CH.sub.2                               N    CH   2-trifluoromethylphenyl     396  1     OH        CH.sub.2                               N    CH   amino     397  1     OH        CH.sub.2                               N    CH   amidino     398  1     OH        CH.sub.2                               N    CH   guanidino     399  1     OH        CH.sub.2                               N    CH   2-sulfamidophenyl     400  1     OH        CH.sub.2                               N    CH   2-trifluoromethylphenyl     401  1     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   amino     402  1     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   amidino     403  1     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   guanidino     404  1     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   2-sulfamidophenyl     405  1     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     406  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   amino     407  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   amidino     408  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   guanidino     409  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   2-sulfamidophenyl     410  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     411  1     OCH.sub.3 CH.sub.2                               N    CH   amino     412  1     OCH.sub.3 CH.sub.2                               N    CH   amidino     413  1     OCH.sub.3 CH.sub.2                               N    CH   guanidino     414  1     OCH.sub.3 CH.sub.2                               N    CH   2-sulfamidophenyl     415  1     OCH.sub.3 CH.sub.2                               N    CH   2-trifluoromethylphenyl     416  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   amino     417  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   amidino     418  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   guanidino     419  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   2-sulfamidophenyl     420  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     421  1     H         bond N    N    amino     422  1     H         bond N    N    amidino     423  1     H         bond N    N    guanidino     424  1     H         bond N    N    2-sulfamidophenyl     425  1     H         bond N    N    2-trifluoromethylphenyl     426  1     OH        bond N    N    amino     427  1     OH        bond N    N    amidino     428  1     OH        bond N    N    guanidino     429  1     OH        bond N    N    2-sulfamidophenyl     430  1     OH        bond N    N    2-trifluoromethylphenyl     431  1     NHC(O)CH.sub.3                          bond N    N    amino     432  1     NHC(O)CH.sub.3                          bond N    N    amidino     433  1     NHC(O)CH.sub.3                          bond N    N    guanidino     434  1     NHC(O)CH.sub.3                          bond N    N    2-sulfamidophenyl     435  1     NHC(O)CH.sub.3                          bond N    N    2-trifluoromethylphenyl     436  1     NHSO.sub.2 CH.sub.3                          bond N    N    amino     437  1     NHSO.sub.2 CH.sub.3                          bond N    N    amidino     438  1     NHSO.sub.2 CH.sub.3                          bond N    N    guanidino     439  1     NHSO.sub.2 CH.sub.3                          bond N    N    2-sulfamidophenyl     440  1     NHSO.sub.2 CH.sub.3                          bond N    N    2-trifluoromethylphenyl     441  1     OCH.sub.3 bond N    N    amino     442  1     OCH.sub.3 bond N    N    amidino     443  1     OCH.sub.3 bond N    N    guanidino     444  1     OCH.sub.3 bond N    N    2-sulfamidophenyl     445  1     OCH.sub.3 bond N    N    2-trifluoromethylphenyl     446  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    amino     447  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    amidino     448  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    guanidino     449  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    2-sulfamidophenyl     450  1     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    2-trifluoromethylphenyl     451  1     H         CH.sub.2                               N    N    amino     452  1     H         CH.sub.2                               N    N    amidino     453  1     H         CH.sub.2                               N    N    guanidino     454  1     H         CH.sub.2                               N    N    2-sulfamidophenyl     455  1     H         CH.sub.2                               N    N    2-trifluoromethylphenyl     456  1     OH        CH.sub.2                               N    N    amino     457  1     OH        CH.sub.2                               N    N    amidino     458  1     OH        CH.sub.2                               N    N    guanidino     459  1     OH        CH.sub.2                               N    N    2-sulfamidophenyl     460  1     OH        CH.sub.2                               N    N    2-trifluoromethylphenyl     461  1     NHC(O)CH.sub.3                          CH.sub.2                               N    N    amino     462  1     NHC(O)CH.sub.3                          CH.sub.2                               N    N    amidino     463  1     NHC(O)CH.sub.3                          CH.sub.2                               N    N    guanidino     464  1     NHC(O)CH.sub.3                          CH.sub.2                               N    N    2-sulfamidophenyl     465  1     NHC(O)CH.sub.3                          CH.sub.2                               N    N    2-trifluoromethylphenyl     466  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    amino     467  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    amidino     468  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    guanidino     469  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    2-sulfamidophenyl     470  1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    2-trifluoromethylphenyl     471  1     OCH.sub.3 CH.sub.2                               N    N    amino     472  1     OCH.sub.3 CH.sub.2                               N    N    amidino     473  1     OCH.sub.3 CH.sub.2                               N    N    guanidino     474  1     OCH.sub.3 CH.sub.2                               N    N    2-sulfamidophenyl     475  1     OCH.sub.3 CH.sub.2                               N    N    2-trifluoromethylphenyl     476  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    amino     477  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    amidino     478  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    guanidino     479  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    2-sulfamidophenyl     480  1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    2-trifluoromethylphenyl     ______________________________________

                  TABLE 10     ______________________________________     1 #STR31##     Ex.  n     R.sup.2   Z    A.sup.1                                    A.sup.2                                         B     ______________________________________     501  2     H         bond CH   CH   amino     502  2     H         bond CH   CH   guanidino     503  2     H         bond CH   CH   2-sulfamidophenyl     504  2     H         bond CH   CH   2-trifluoromethylphenyl     505  2     OH        bond CH   CH   amino     506  2     OH        bond CH   CH   amidino     507  2     OH        bond CH   CH   guanidino     508  2     OH        bond CH   CH   2-sulfamidophenyl     509  2     OH        bond CH   CH   2-trifluoromethylphenyl     510  2     NHC(O)CH.sub.3                          bond CH   CH   amino     511  2     NHC(O)CH.sub.3                          bond CH   CH   amidino     512  2     NHC(O)CH.sub.3                          bond CH   CH   guanidino     513  2     NHC(O)CH.sub.3                          bond CH   CH   2-sulfamidophenyl     514  2     NHC(O)CH.sub.3                          bond CH   CH   2-trifluoromethylphenyl     515  2     NHSO.sub.2 CH.sub.3                          bond CH   CH   amino     516  2     NHSO.sub.2 CH.sub.3                          bond CH   CH   amidino     517  2     NHSO.sub.2 CH.sub.3                          bond CH   CH   guanidino     518  2     NHSO.sub.2 CH.sub.3                          bond CH   CH   2-sulfamidophenyl     519  2     NHSO.sub.2 CH.sub.3                          bond CH   CH   2-trifluoromethylphenyl     520  2     OCH.sub.3 bond CH   CH   amino     521  2     OCH.sub.3 bond CH   CH   amidino     522  2     OCH.sub.3 bond CH   CH   guanidino     523  2     OCH.sub.3 bond CH   CH   2-sulfamidophenyl     524  2     OCH.sub.3 bond CH   CH   2-trifluoromethylphenyl     525  2     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   amino     526  2     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   amidino     527  2     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   guanidino     528  2     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   2-sulfamidophenyl     529  2     OCH.sub.2 C.sub.6 H.sub.5                          bond CH   CH   2-trifluoromethylphenyl     530  2     H         CH.sub.2                               CH   CH   amino     531  2     H         CH.sub.2                               CH   CH   guanidino     532  2     H         CH.sub.2                               CH   CH   2-sulfamidophenyl     533  2     H         CH.sub.2                               CH   CH   2-trifluoromethylphenyl     534  2     OH        CH.sub.2                               CH   CH   amino     535  2     OH        CH.sub.2                               CH   CH   amidino     536  2     OH        CH.sub.2                               CH   CH   guanidino     537  2     OH        CH.sub.2                               CH   CH   2-sulfamidophenyl     538  2     OH        CH.sub.2                               CH   CH   2-trifluoromethylphenyl     539  2     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   amino     540  2     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   amidino     541  2     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   guanidino     542  2     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   2-sulfamidophenyl     543  2     NHC(O)CH.sub.3                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     544  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   amino     545  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   amidino     546  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   guanidino     547  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   2-sulfamidophenyl     548  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     549  2     OCH.sub.3 CH.sub.2                               CH   CH   amino     550  2     OCH.sub.3 CH.sub.2                               CH   CH   amidino     551  2     OCH.sub.3 CH.sub.2                               CH   CH   guanidino     552  2     OCH.sub.3 CH.sub.2                               CH   CH   2-sulfamidophenyl     553  2     OCH.sub.3 CH.sub.2                               CH   CH   2-trifluoromethylphenyl     554  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   amino     555  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   amidino     556  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   guanidino     557  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   2-sulfamidophenyl     558  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               CH   CH   2-trifluoromethylphenyl     559  2     H         bond N    CH   amino     560  2     H         bond N    CH   amidino     561  2     H         bond N    CH   guanidino     562  2     H         bond N    CH   2-sulfamidophenyl     563  2     H         bond N    CH   2-trifluoromethylphenyl     564  2     OH        bond N    CH   amino     565  2     OH        bond N    CH   amidino     566  2     OH        bond N    CH   guanidino     567  2     OH        bond N    CH   2-sulfamidophenyl     568  2     OH        bond N    CH   2-trifluoromethylphenyl     569  2     NHC(O)CH.sub.3                          bond N    CH   amino     570  2     NHC(O)CH.sub.3                          bond N    CH   amidino     571  2     NHC(O)CH.sub.3                          bond N    CH   guanidino     572  2     NHC(O)CH.sub.3                          bond N    CH   2-sulfamidophenyl     573  2     NHC(O)CH.sub.3                          bond N    CH   2-trifluoromethylphenyl     574  2     NHSO.sub.2 CH.sub.3                          bond N    CH   amino     575  2     NHSO.sub.2 CH.sub.3                          bond N    CH   amidino     576  2     NHSO.sub.2 CH.sub.3                          bond N    CH   guanidino     577  2     NHSO.sub.2 CH.sub.3                          bond N    CH   2-sulfamidophenyl     578  2     NHSO.sub.2 CH.sub.3                          bond N    CH   2-trifluoromethylphenyl     579  2     OCH.sub.3 bond N    CH   amino     580  2     OCH.sub.3 bond N    CH   amidino     581  2     OCH.sub.3 bond N    CH   guanidino     582  2     OCH.sub.3 bond N    CH   2-sulfamidophenyl     583  2     OCH.sub.3 bond N    CH   2-trifluoromethylphenyl     584  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   amino     585  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   amidino     586  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   guanidino     587  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   2-sulfamidophenyl     588  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    CH   2-trifluoromethylphenyl     589  2     H         CH.sub.2                               N    CH   amino     590  2     H         CH.sub.2                               N    CH   amidino     591  2     H         CH.sub.2                               N    CH   guanidino     592  2     H         CH.sub.2                               N    CH   2-sulfamidophenyl     593  2     H         CH.sub.2                               N    CH   2-trifluoromethylphenyl     594  2     OH        CH.sub.2                               N    CH   amino     595  2     OH        CH.sub.2                               N    CH   amidino     596  2     OH        CH.sub.2                               N    CH   guanidino     597  2     OH        CH.sub.2                               N    CH   2-sulfamidophenyl     598  2     OH        CH.sub.2                               N    CH   2-trifluoromethylphenyl     599  2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   amino     600  2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   amidino     601  2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   guanidino     602  2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   2-sulfamidophenyl     603  2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     604  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   amino     605  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   amidino     606  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   guanidino     607  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   2-sulfamidophenyl     608  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     609  2     OCH.sub.3 CH.sub.2                               N    CH   amino     610  2     OCH.sub.3 CH.sub.2                               N    CH   amidino     611  2     OCH.sub.3 CH.sub.2                               N    CH   guanidino     612  2     OCH.sub.3 CH.sub.2                               N    CH   2-sulfamidophenyl     613  2     OCH.sub.3 CH.sub.2                               N    CH   2-trifluoromethylphenyl     614  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   amino     615  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   amidino     616  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   guanidino     617  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   2-sulfamidophenyl     618  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    CH   2-trifluoromethylphenyl     619  2     H         bond N    N    amino     620  2     H         bond N    N    amidino     621  2     H         bond N    N    guanidino     622  2     H         bond N    N    2-sulfamidophenyl     623  2     H         bond N    N    2-trifluoromethylphenyl     624  2     OH        bond N    N    amino     625  2     OH        bond N    N    amidino     626  2     OH        bond N    N    guanidino     627  2     OH        bond N    N    2-sulfamidophenyl     628  2     OH        bond N    N    2-trifluoromethylphenyl     629  2     NHC(O)CH.sub.3                          bond N    N    amino     630  2     NHC(O)CH.sub.3                          bond N    N    amidino     631  2     NHC(O)CH.sub.3                          bond N    N    guanidino     632  2     NHC(O)CH.sub.3                          bond N    N    2-sulfamidophenyl     633  2     NHC(O)CH.sub.3                          bond N    N    2-trifluoromethylphenyl     634  2     NHSO.sub.2 CH.sub.3                          bond N    N    amino     635  2     NHSO.sub.2 CH.sub.3                          bond N    N    amidino     636  2     NHSO.sub.2 CH.sub.3                          bond N    N    guanidino     637  2     NHSO.sub.2 CH.sub.3                          bond N    N    2-sulfamidophenyl     638  2     NHSO.sub.2 CH.sub.3                          bond N    N    2-trifluoromethylphenyl     639  2     OCH.sub.3 bond N    N    amino     640  2     OCH.sub.3 bond N    N    amidino     641  2     OCH.sub.3 bond N    N    guanidino     642  2     OCH.sub.3 bond N    N    2-sulfamidophenyl     643  2     OCH.sub.3 bond N    N    2-trifluoromethylphenyl     644  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    amino     645  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    amidino     646  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    guanidino     647  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    2-sulfamidophenyl     648  2     OCH.sub.2 C.sub.6 H.sub.5                          bond N    N    2-trifluoromethylphenyl     649  2     H         CH.sub.2                               N    N    amino     650  2     H         CH.sub.2                               N    N    amidino     651  2     H         CH.sub.2                               N    N    guanidino     652  2     H         CH.sub.2                               N    N    2-sulfamidophenyl     653  2     H         CH.sub.2                               N    N    2-trifluoromethylphenyl     654  2     OH        CH.sub.2                               N    N    amino     655  2     OH        CH.sub.2                               N    N    amidino     656  2     OH        CH.sub.2                               N    N    guanidino     657  2     OH        CH.sub.2                               N    N    2-sulfamidophenyl     658  2     OH        CH.sub.2                               N    N    2-trifluoromethylphenyl     659  2     NHC(O)CH.sub.3                          CH.sub.2                               N    N    amino     660  2     NHC(O)CH.sub.3                          CH.sub.2                               N    N    amidino     661  2     NHC(O)CH.sub.3                          CH.sub.2                               N    N    guanidino     662  2     NHC(O)CH.sub.3                          CH.sub.2                               N    N    2-sulfamidophenyl     663  2     NHC(O)CH.sub.3                          CH.sub.2                               N    N    2-trifluoromethylphenyl     664  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    amino     665  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    amidino     666  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    guanidino     667  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    2-sulfamidophenyl     668  2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    N    2-trifluoromethylphenyl     669  2     OCH.sub.3 CH.sub.2                               N    N    amino     670  2     OCH.sub.3 CH.sub.2                               N    N    amidino     671  2     OCH.sub.3 CH.sub.2                               N    N    guanidino     672  2     OCH.sub.3 CH.sub.2                               N    N    2-sulfamidophenyl     673  2     OCH.sub.3 CH.sub.2                               N    N    2-trifluoromethylphenyl     674  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    amino     675  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    amidino     676  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    guanidino     677  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    2-sulfamidophenyl     678  2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    2-trifluoromethylphenyl     ______________________________________

                  TABLE 11     ______________________________________     2 #STR32##     Ex.  n     R.sup.2   Z    A.sup.1                                   A.sup.2                                       B     ______________________________________     701  0     H         bond CH  CH  imidazol-1-yl     702  0     H         bond CH  CH  morpholin-1-yl     703  0     H         bond CH  CH  2-methylimidazol-1-yl     704  0     H         bond CH  CH  pyridin-3-yl     705  0     H         bond CH  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     706  0     H         bond CH  CH  pyrazol-1-yl     707  0     H         bond CH  CH  phenyl     708  0     H         bond CH  CH  cyclohexyl     709  0     H         bond CH  CH  N,N-dimethylsulfamido     710  0     H         bond CH  CH  N,N-dimethylamido     711  0     H         bond N   CH  imidazol-1-yl     712  0     H         bond N   CH  morpholin-1-yl     713  0     H         bond N   CH  2-methylimidazol-1-yl     714  0     H         bond N   CH  pyridin-3-yl     715  0     H         bond N   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     716  0     H         bond N   CH  pyrazol-1-yl     717  0     H         bond N   CH  phenyl     718  0     H         bond N   CH  cyclohexyl     719  0     H         bond N   CH  N,N-dimethylsulfamido     720  0     H         bond N   CH  N,N-dimethylamido     721  0     H         bond N   N   imidazol-1-yl     722  0     H         bond N   N   morpholin-1-yl     723  0     H         bond N   N   2-methylimidazol-1-yl     724  0     H         bond N   N   pyridin-3-yl     725  0     H         bond N   N   2-(5'-trifluoromethyl) tetrazol- 1'-yl     726  0     H         bond N   N   pyrazol-1-yl     727  0     H         bond N   N   phenyl     728  0     H         bond N   N   cyclohexyl     729  0     H         bond N   N   N,N-dimethylsulfamido     730  0     H         bond N   N   N,N-dimethylamido     731  0     H         bond F   CH  imidazol-1-yl     732  0     H         bond F   CH  morpholin-1-yl     733  0     H         bond F   CH  2-methylimidazol-1-yl     734  0     H         bond F   CH  pyridin-3-yl     735  0     H         bond F   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     736  0     H         bond F   CH  pyrazol-1-yl     737  0     H         bond F   CH  phenyl     738  0     H         bond F   CH  cyclohexyl     739  0     H         bond F   CH  N,N-dimethylsulfamido     740  0     H         bond F   CH  N,N-dimethylamido     741  0     H         bond Cl  CH  imidazol-1-yl     742  0     H         bond Cl  CH  morpholin-1-yl     743  0     H         bond Cl  CH  2-methylimidazol-1-yl     744  0     H         bond Cl  CH  pyridin-3-yl     745  0     H         bond Cl  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     746  0     H         bond Cl  CH  pyrazol-1-yl     747  0     H         bond Cl  CH  phenyl     748  0     H         bond Cl  CH  cyclohexyl     749  0     H         bond Cl  CH  N,N-dimethylsulfamido     750  0     H         bond Cl  CH  N,N-dimethylamido     751  0     H         bond Br  CH  imidazol-1-yl     752  0     H         bond Br  CH  morpholin-1-yl     753  0     H         bond Br  CH  2-methylimidazol-1-yl     754  0     H         bond Br  CH  pyridin-3-yl     755  0     H         bond Br  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     756  0     H         bond Br  CH  pyrazol-1-yl     757  0     H         bond Br  CH  phenyl     758  0     H         bond Br  CH  cyclohexyl     759  0     H         bond Br  CH  N,N-dimethylsulfamido     760  0     H         bond Br  CH  N,N-dimethylamido     761  0     H         CH.sub.2                               CH  CH  imidazol-1-yl     762  0     H         CH.sub.2                               CH  CH  morpholin-1-yl     763  0     H         CH.sub.2                               CH  CH  2-methylimidazol-1-yl     764  0     H         CH.sub.2                               CH  CH  pyridin-3-yl     765  0     H         CH.sub.2                               CH  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     766  0     H         CH.sub.2                               CH  CH  pyrazol-1-yl     767  0     H         CH.sub.2                               CH  CH  phenyl     768  0     H         CH.sub.2                               CH  CH  cyclohexyl     769  0     H         CH.sub.2                               CH  CH  N,N-dimethylsulfamido     770  0     H         CH.sub.2                               CH  CH  N,N-dimethylamido     771  0     H         CH.sub.2                               N   CH  imidazol-1-yl     772  0     H         CH.sub.2                               N   CH  morpholin-1-yl     773  0     H         CH.sub.2                               N   CH  2-methylimidazol-1-yl     774  0     H         CH.sub.2                               N   CH  pyridin-3-yl     775  0     H         CH.sub.2                               N   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     776  0     H         CH.sub.2                               N   CH  pyrazol-1-yl     777  0     H         CH.sub.2                               N   CH  phenyl     778  0     H         CH.sub.2                               N   CH  cyclohexyl     779  0     H         CH.sub.2                               N   CH  N,N-dimethylsulfamido     780  0     H         CH.sub.2                               N   CH  N,N-dimethylamido     781  0     H         CH.sub.2                               N   N   imidazol-1-yl     782  0     H         CH.sub.2                               N   N   morpholin-1-yl     783  0     H         CH.sub.2                               N   N   2-methylimidazol-1-yl     784  0     H         CH.sub.2                               N   N   pyridin-3-yl     785  0     H         CH.sub.2                               N   N   2-(5'-trifluoromethyl) tetrazol- 1'-yl     786  0     H         CH.sub.2                               N   N   pyrazol-1-yl     787  0     H         CH.sub.2                               N   N   phenyl     788  0     H         CH.sub.2                               N   N   cyclohexyl     789  0     H         CH.sub.2                               N   N   N,N-dimethylsulfamido     790  0     H         CH.sub.2                               N   N   N,N-dimethylamido     791  0     H         CH.sub.2                               F   CH  imidazol-1-yl     792  0     H         CH.sub.2                               F   CH  morpholin-1-yl     793  0     H         CH.sub.2                               F   CH  2-methylimidazol-1-yl     794  0     H         CH.sub.2                               F   CH  pyridin-3-yl     795  0     H         CH.sub.2                               F   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     796  0     H         CH.sub.2                               F   CH  pyrazol-1-yl     797  0     H         CH.sub.2                               F   CH  phenyl     798  0     H         CH.sub.2                               F   CH  cyclohexyl     799  0     H         CH.sub.2                               F   CH  N,N-dimethylsulfamido     800  0     H         CH.sub.2                               F   CH  N,N-dimethylamido     801  0     H         CH.sub.2                               Cl  CH  imidazol-1-yl     802  0     H         CH.sub.2                               Cl  CH  morpholin-1-yl     803  0     H         CH.sub.2                               Cl  CH  2-methylimidazol-1-yl     804  0     H         CH.sub.2                               Cl  CH  pyridin-3-yl     805  0     H         CH.sub.2                               Cl  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     806  0     H         CH.sub.2                               Cl  CH  pyrazol-1-yl     807  0     H         CH.sub.2                               Cl  CH  phenyl     808  0     H         CH.sub.2                               Cl  CH  cyclohexyl     809  0     H         CH.sub.2                               Cl  CH  N,N-dimethylsulfamido     810  0     H         CH.sub.2                               Cl  CH  N,N-dimethylamido     811  0     H         CH.sub.2                               Br  CH  imidazol-1-yl     812  0     H         CH.sub.2                               Br  CH  morpholin-1-yl     813  0     H         CH.sub.2                               Br  CH  2-methylimidazol-1-yl     814  0     H         CH.sub.2                               Br  CH  pyridin-3-yl     815  0     H         CH.sub.2                               Br  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     816  0     H         CH.sub.2                               Br  CH  pyrazol-1-yl     817  0     H         CH.sub.2                               Br  CH  phenyl     818  0     H         CH.sub.2                               Br  CH  cyclohexyl     819  0     H         CH.sub.2                               Br  CH  N,N-dimethylsulfamido     820  0     H         CH.sub.2                               Br  CH  N,N-dimethylamido     821  0     OH        bond F   CH  pyrazol-1-yl     822  0     OH        bond F   CH  phenyl     823  0     OH        bond F   CH  cyclohexyl     824  0     OH        bond F   CH  N,N-dimethylsulfamido     825  0     OH        bond F   CH  N,N-dimethylamido     826  0     NHC(O)CH.sub.3                          bond Cl  CH  imidazol-1-yl     827  0     NHC(O)CH.sub.3                          bond Cl  CH  morpholin-1-yl     828  0     NHC(O)CH.sub.3                          bond Cl  CH  2-methylimidazol-1-yl     829  0     NHC(O)CH.sub.3                          bond Cl  CH  pyridin-3-yl     830  0     NHC(O)CH.sub.3                          bond Cl  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     831  0     NHSO.sub.2 CH.sub.3                          bond Cl  CH  pyrazol-1-yl     832  0     NHSO.sub.2 CH.sub.3                          bond Cl  CH  phenyl     833  0     NHSO.sub.2 CH.sub.3                          bond Cl  CH  cyclohexyl     834  0     NHSO.sub.2 CH.sub.3                          bond Cl  CH  N,N-dimethylsulfamido     835  0     NHSO.sub.2 CH.sub.3                          bond Cl  CH  N,N-dimethylamido     836  0     OCH.sub.3 bond Br  CH  imidazol-1-yl     837  0     OCH.sub.3 bond Br  CH  morpholin-1-yl     838  0     OCH.sub.3 bond Br  CH  2-methylimidazol-1-yl     839  0     OCH.sub.3 bond Br  CH  pyridin-3-yl     840  0     OCH.sub.3 bond Br  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     841  0     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  pyrazol-1-yl     842  0     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  phenyl     843  0     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  cyclohexyl     844  0     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  N,N-dimethylsulfamido     845  0     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  N,N-dimethylamido     846  0     OH        CH.sub.2                               CH  CH  pyrazol-1-yl     847  0     OH        CH.sub.2                               CH  CH  phenyl     848  0     OH        CH.sub.2                               CH  CH  cyclohexyl     849  0     OH        CH.sub.2                               CH  CH  N,N-dimethylsulfamido     850  0     OH        CH.sub.2                               CH  CH  N,N-dimethylamido     851  0     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  imidazol-1-yl     852  0     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  morpholin-1-yl     853  0     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  2-methylimidazol-1-yl     854  0     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  pyridin-3-yl     855  0     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     856  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  pyrazol-1-yl     857  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  phenyl     858  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  cyclohexyl     859  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  N,N-dimethylsulfamido     860  0     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  N,N-dimethylamido     861  0     OCH.sub.3 CH.sub.2                               N   N   imidazol-1-yl     862  0     OCH.sub.3 CH.sub.2                               N   N   morpholin-1-yl     863  0     OCH.sub.3 CH.sub.2                               N   N   2-methylimidazol-1-yl     864  0     OCH.sub.3 CH.sub.2                               N   N   pyridin-3-yl     865  0     OCH.sub.3 CH.sub.2                               N   N   2-(5'-trifluoromethyl) tetrazol- 1'-yl     866  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   pyrazol-1-yl     867  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   phenyl     868  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   cyclohexyl     869  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   N,N-dimethylsulfamido     870  0     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   N,N-dimethylamido     ______________________________________

                  TABLE 12     ______________________________________     3 #STR33##     Ex.  n     R.sup.2   Z    A.sup.1                                   A.sup.2                                       B     ______________________________________      901 1     H         bond CH  CH  imidazol-1-yl      902 1     H         bond CH  CH  morpholin-1-yl      903 1     H         bond CH  CH  2-methylimidazol-1-yl      904 1     H         bond CH  CH  pyridin-3-yl      905 1     H         bond CH  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl      906 1     H         bond CH  CH  pyrazol-1-yl      907 1     H         bond CH  CH  phenyl      908 1     H         bond CH  CH  cyclohexyl      909 1     H         bond CH  CH  N,N-dimethylsulfamido      910 1     H         bond CH  CH  N,N-dimethylamido      911 1     H         bond N   CH  imidazol-1-yl      912 1     H         bond N   CH  morpholin-1-yl      913 1     H         bond N   CH  2-methylimidazol-1-yl      914 1     H         bond N   CH  pyridin-3-yl      915 1     H         bond N   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl      916 1     H         bond N   CH  pyrazol-1-yl      917 1     H         bond N   CH  phenyl      918 1     H         bond N   CH  cyclohexyl      919 1     H         bond N   CH  N,N-dimethylsulfamido      920 1     H         bond N   CH  N,N-dimethylamido      921 1     H         bond N   N   imidazol-1-yl      922 1     H         bond N   N   morpholin-1-yl      923 1     H         bond N   N   2-methylimidazol-1-yl      924 1     H         bond N   N   pyridin-3-yl      925 1     H         bond N   N   2-(5'-trifluoromethyl) tetrazol- 1'-yl      926 1     H         bond N   N   pyrazol-1-yl      927 1     H         bond N   N   phenyl      928 1     H         bond N   N   cyclohexyl      929 1     H         bond N   N   N,N-dimethylsulfamido      930 1     H         bond N   N   N,N-dimethylamido      931 1     H         bond F   CH  imidazol-1-yl      932 1     H         bond F   CH  morpholin-1-yl      933 1     H         bond F   CH  2-methylimidazol-1-yl      934 1     H         bond F   CH  pyridin-3-yl      935 1     H         bond F   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl      936 1     H         bond F   CH  pyrazol-1-yl      937 1     H         bond F   CH  phenyl      938 1     H         bond F   CH  cyclohexyl      939 1     H         bond F   CH  N,N-dimethylsulfamido      940 1     H         bond F   CH  N,N-dimethylamido      941 1     H         bond Cl  CH  imidazol-1-yl      942 1     H         bond Cl  CH  morpholin-1-yl      943 1     H         bond Cl  CH  2-methylimidazol-1-yl      944 1     H         bond Cl  CH  pyridin-3-yl      945 1     H         bond Cl  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl      946 1     H         bond Cl  CH  pyrazol-1-yl      947 1     H         bond Cl  CH  phenyl      948 1     H         bond Cl  CH  cyclohexyl      949 1     H         bond Cl  CH  N,N-dimethylsulfamido      950 1     H         bond Cl  CH  N,N-dimethylamido      951 1     H         bond Br  CH  imidazol-1-yl      952 1     H         bond Br  CH  morpholin-1-yl      953 1     H         bond Br  CH  2-methylimidazol-1-yl      954 1     H         bond Br  CH  pyridin-3-yl      955 1     H         bond Br  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl      956 1     H         bond Br  CH  pyrazol-1-yl      957 1     H         bond Br  CH  phenyl      958 1     H         bond Br  CH  cyclohexyl      959 1     H         bond Br  CH  N,N-dimethylsulfamido      960 1     H         bond Br  CH  N,N-dimethylamido      961 1     H         CH.sub.2                               CH  CH  imidazol-1-yl      962 1     H         CH.sub.2                               CH  CH  morpholin-1-yl      963 1     H         CH.sub.2                               CH  CH  2-methylimidazol-1-yl      964 1     H         CH.sub.2                               CH  CH  pyridin-3-yl      965 1     H         CH.sub.2                               CH  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl      966 1     H         CH.sub.2                               CH  CH  pyrazol-1-yl      967 1     H         CH.sub.2                               CH  CH  phenyl      968 1     H         CH.sub.2                               CH  CH  cyclohexyl      969 1     H         CH.sub.2                               CH  CH  N,N-dimethylsulfamido      970 1     H         CH.sub.2                               CH  CH  N,N-dimethylamido      971 1     H         CH.sub.2                               N   CH  imidazol-1-yl      972 1     H         CH.sub.2                               N   CH  morpholin-1-yl      973 1     H         CH.sub.2                               N   CH  2-methylimidazol-1-yl      974 1     H         CH.sub.2                               N   CH  pyridin-3-yl      975 1     H         CH.sub.2                               N   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl      976 1     H         CH.sub.2                               N   CH  pyrazol-1-yl      977 1     H         CH.sub.2                               N   CH  phenyl      978 1     H         CH.sub.2                               N   CH  cyclohexyl      979 1     H         CH.sub.2                               N   CH  N,N-dimethylsulfamido      980 1     H         CH.sub.2                               N   CH  N,N-dimethylamido      981 1     H         CH.sub.2                               N   N   imidazol-1-yl      982 1     H         CH.sub.2                               N   N   morpholin-1-yl      983 1     H         CH.sub.2                               N   N   2-methylimidazol-1-yl      984 1     H         CH.sub.2                               N   N   pyridin-3-yl      985 1     H         CH.sub.2                               N   N   2-(5'-trifluoromethyl) tetrazol- 1'-yl      986 1     H         CH.sub.2                               N   N   pyrazol-1-yl      987 1     H         CH.sub.2                               N   N   phenyl      988 1     H         CH.sub.2                               N   N   cyclohexyl      989 1     H         CH.sub.2                               N   N   N,N-dimethylsulfamido      990 1     H         CH.sub.2                               N   N   N,N-dimethylamido      991 1     H         CH.sub.2                               F   CH  imidazol-1-yl      992 1     H         CH.sub.2                               F   CH  morpholin-1-yl      993 1     H         CH.sub.2                               F   CH  2-methylimidazol-1-yl      994 1     H         CH.sub.2                               F   CH  pyridin-3-yl      995 1     H         CH.sub.2                               F   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl      996 1     H         CH.sub.2                               F   CH  pyrazol-1-yl      997 1     H         CH.sub.2                               F   CH  phenyl      998 1     H         CH.sub.2                               F   CH  cyclohexyl      999 1     H         CH.sub.2                               F   CH  N,N-dimethylsulfamido     1000 1     H         CH.sub.2                               F   CH  N,N-dimethylamido     1001 1     H         CH.sub.2                               Cl  CH  imidazol-1-yl     1002 1     H         CH.sub.2                               Cl  CH  morpholin-1-yl     1003 1     H         CH.sub.2                               Cl  CH  2-methylimidazol-1-yl     1004 1     H         CH.sub.2                               Cl  CH  pyridin-3-yl     1005 1     H         CH.sub.2                               Cl  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     1006 1     H         CH.sub.2                               Cl  CH  pyrazol-1-yl     1007 1     H         CH.sub.2                               Cl  CH  phenyl     1008 1     H         CH.sub.2                               Cl  CH  cyclohexyl     1009 1     H         CH.sub.2                               Cl  CH  N,N-dimethylsulfamido     1010 1     H         CH.sub.2                               Cl  CH  N,N-dimethylamido     1011 1     H         CH.sub.2                               Br  CH  imidazol-1-yl     1012 1     H         CH.sub.2                               Br  CH  morpholin-1-yl     1013 1     H         CH.sub.2                               Br  CH  2-methylimidazol-1-yl     1014 1     H         CH.sub.2                               Br  CH  pyridin-3-yl     1015 1     H         CH.sub.2                               Br  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     1016 1     H         CH.sub.2                               Br  CH  pyrazol-1-yl     1017 1     H         CH.sub.2                               Br  CH  phenyl     1018 1     H         CH.sub.2                               Br  CH  cyclohexyl     1019 1     H         CH.sub.2                               Br  CH  N,N-dimethylsulfamido     1020 1     H         CH.sub.2                               Br  CH  N,N-dimethylamido     1021 1     OH        bond F   CH  pyrazol-1-yl     1022 1     OH        bond F   CH  phenyl     1023 1     OH        bond F   CH  cyclohexyl     1024 1     OH        bond F   CH  N,N-dimethylsulfamido     1025 1     OH        bond F   CH  N,N-dimethylamido     1026 1     NHC(O)CH.sub.3                          bond Cl  CH  imidazol-1-yl     1027 1     NHC(O)CH.sub.3                          bond Cl  CH  morpholin-1-yl     1028 1     NHC(O)CH.sub.3                          bond Cl  CH  2-methylimidazol-1-yl     1029 1     NHC(O)CH.sub.3                          bond Cl  CH  pyridin-3-yl     1030 1     NHC(O)CH.sub.3                          bond Cl  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     1031 1     NHSO.sub.2 CH.sub.3                          bond Cl  CH  pyrazol-1-yl     1032 1     NHSO.sub.2 CH.sub.3                          bond Cl  CH  phenyl     1033 1     NHSO.sub.2 CH.sub.3                          bond Cl  CH  cyclohexyl     1034 1     NHSO.sub.2 CH.sub.3                          bond Cl  CH  N,N-dimethylsulfamido     1035 1     NHSO.sub.2 CH.sub.3                          bond Cl  CH  N,N-dimethylamido     1036 1     OCH.sub.3 bond Br  CH  imidazol-1-yl     1037 1     OCH.sub.3 bond Br  CH  morpholin-1-yl     1038 1     OCH.sub.3 bond Br  CH  2-methylimidazol-1-yl     1039 1     OCH.sub.3 bond Br  CH  pyridin-3-yl     1040 1     OCH.sub.3 bond Br  CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     1041 1     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  pyrazol-1-yl     1042 1     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  phenyl     1043 1     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  cyclohexyl     1044 1     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  N,N-dimethylsulfamido     1045 1     OCH.sub.2 C.sub.6 H.sub.5                          bond Br  CH  N,N-dimethylamido     1046 1     OH        CH.sub.2                               CH  CH  pyrazol-1-yl     1047 1     OH        CH.sub.2                               CH  CH  phenyl     1048 1     OH        CH.sub.2                               CH  CH  cyclohexyl     1049 1     OH        CH.sub.2                               CH  CH  N,N-dimethylsulfamido     1050 1     OH        CH.sub.2                               CH  CH  N,N-dimethylamido     1051 1     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  imidazol-1-yl     1052 1     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  morpholin-1-yl     1053 1     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  2-methylimidazol-1-yl     1054 1     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  pyridin-3-yl     1055 1     NHC(O)CH.sub.3                          CH.sub.2                               N   CH  2-(5'-trifluoromethyl) tetrazol- 1'-yl     1056 1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  pyrazol-1-yl     1057 1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  phenyl     1058 1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  cyclohexyl     1059 1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  N,N-dimethylsulfamido     1060 1     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N   CH  N,N-dimethylamido     1061 1     OCH.sub.3 CH.sub.2                               N   N   imidazol-1-yl     1062 1     OCH.sub.3 CH.sub.2                               N   N   morpholin-1-yl     1063 1     OCH.sub.3 CH.sub.2                               N   N   2-methylimidazol-1-yl     1064 1     OCH.sub.3 CH.sub.2                               N   N   pyridin-3-yl     1065 1     OCH.sub.3 CH.sub.2                               N   N   2-(5'-trifluoromethyl) tetrazol- 1'-yl     1066 1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   pyrazol-1-yl     1067 1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   phenyl     1068 1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   cyclohexyl     1069 1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   N,N-dimethylsulfamido     1070 1     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N   N   N,N-dimethylamido     ______________________________________

                  TABLE 13     ______________________________________     1 #STR34##     Ex.  n     R.sup.2   Z    A.sup.1                                    A.sup.2                                         B     ______________________________________     1101 2     H         bond CH   CH   imidazol-1-yl     1102 2     H         bond CH   CH   morpholin-1-yl     1103 2     H         bond CH   CH   2-methylimidazol-1-yl     1104 2     H         bond CH   CH   pyridin-3-yl     1105 2     H         bond CH   CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1106 2     H         bond CH   CH   pyrazol-1-yl     1107 2     H         bond CH   CH   phenyl     1108 2     H         bond CH   CH   cyclohexyl     1109 2     H         bond CH   CH   N,N-dimethylsulfamido     1110 2     H         bond CH   CH   N,N-dimethylamido     1111 2     H         bond N    CH   imidazol-1-yl     1112 2     H         bond N    CH   morpholin-1-yl     1113 2     H         bond N    CH   2-methylimidazol-1-yl     1114 2     H         bond N    CH   pyridin-3-yl     1115 2     H         bond N    CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1116 2     H         bond N    CH   pyrazol-1-yl     1117 2     H         bond N    CH   phenyl     1118 2     H         bond N    CH   cyclohexyl     1119 2     H         bond N    CH   N,N-dimethylsulfamido     1120 2     H         bond N    CH   N,N-dimethylamido     1121 2     H         bond N    N    imidazol-1-yl     1122 2     H         bond N    N    morpholin-1-yl     1123 2     H         bond N    N    2-methylimidazol-1-yl     1124 2     H         bond N    N    pyridin-3-yl     1125 2     H         bond N    N    2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1126 2     H         bond N    N    pyrazol-1-yl     1127 2     H         bond N    N    phenyl     1128 2     H         bond N    N    cyclohexyl     1129 2     H         bond N    N    N,N-dimethylsulfamido     1130 2     H         bond N    N    N,N-dimethylamido     1131 2     H         bond F    CH   imidazol-1-yl     1132 2     H         bond F    CH   morpholin-1-yl     1133 2     H         bond F    CH   2-methylimidazol-1-yl     1134 2     H         bond F    CH   pyridin-3-yl     1135 2     H         bond F    CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1136 2     H         bond F    CH   pyrazol-1-yl     1137 2     H         bond F    CH   phenyl     1138 2     H         bond F    CH   cyclohexyl     1139 2     H         bond F    CH   N,N-dimethylsulfamido     1140 2     H         bond F    CH   N,N-dimethylamido     1141 2     H         bond Cl   CH   imidazol-1-yl     1142 2     H         bond Cl   CH   morpholin-1-yl     1143 2     H         bond Cl   CH   2-methylimidazol-1-yl     1144 2     H         bond Cl   CH   pyridin-3-yl     1145 2     H         bond Cl   CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1146 2     H         bond Cl   CH   pyrazol-1-yl     1147 2     H         bond Cl   CH   phenyl     1148 2     H         bond Cl   CH   cyclohexyl     1149 2     H         bond Cl   CH   N,N-dimethylsulfamido     1150 2     H         bond Cl   CH   N,N-dimethylamido     1151 2     H         bond Br   CH   imidazol-1-yl     1152 2     H         bond Br   CH   morpholin-1-yl     1153 2     H         bond Br   CH   2-methylimidazol-1-yl     1154 2     H         bond Br   CH   pyridin-3-yl     1155 2     H         bond Br   CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1156 2     H         bond Br   CH   pyrazol-1-yl     1157 2     H         bond Br   CH   phenyl     1158 2     H         bond Br   CH   cyclohexyl     1159 2     H         bond Br   CH   N,N-dimethylsulfamido     1160 2     H         bond Br   CH   N,N-dimethylamido     1161 2     H         CH.sub.2                               CH   CH   imidazol-1-yl     1162 2     H         CH.sub.2                               CH   CH   morpholin-1-yl     1163 2     H         CH.sub.2                               CH   CH   2-methylimidazol-1-yl     1164 2     H         CH.sub.2                               CH   CH   pyridin-3-yl     1165 2     H         CH.sub.2                               CH   CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1166 2     H         CH.sub.2                               CH   CH   pyrazol-1-yl     1167 2     H         CH.sub.2                               CH   CH   phenyl     1168 2     H         CH.sub.2                               CH   CH   cyclohexyl     1169 2     H         CH.sub.2                               CH   CH   N,N-dimethylsulfamido     1170 2     H         CH.sub.2                               CH   CH   N,N-dimethylamido     1171 2     H         CH.sub.2                               N    CH   imidazol-1-yl     1172 2     H         CH.sub.2                               N    CH   morpholin-1-yl     1173 2     H         CH.sub.2                               N    CH   2-methylimidazol-1-yl     1174 2     H         CH.sub.2                               N    CH   pyridin-3-yl     1175 2     H         CH.sub.2                               N    CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1176 2     H         CH.sub.2                               N    CH   pyrazol-1-yl     1177 2     H         CH.sub.2                               N    CH   phenyl     1178 2     H         CH.sub.2                               N    CH   cyclohexyl     1179 2     H         CH.sub.2                               N    CH   N,N-dimethylsulfamido     1180 2     H         CH.sub.2                               N    CH   N,N-dimethylamido     1181 2     H         CH.sub.2                               N    N    imidazol-1-yl     1182 2     H         CH.sub.2                               N    N    morpholin-1-yl     1183 2     H         CH.sub.2                               N    N    2-methylimidazol-1-yl     1184 2     H         CH.sub.2                               N    N    pyridin-3-yl     1185 2     H         CH.sub.2                               N    N    2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1186 2     H         CH.sub.2                               N    N    pyrazol-1-yl     1187 2     H         CH.sub.2                               N    N    phenyl     1188 2     H         CH.sub.2                               N    N    cyclohexyl     1189 2     H         CH.sub.2                               N    N    N,N-dimethylsulfamido     1190 2     H         CH.sub.2                               N    N    N,N-dimethylamido     1191 2     H         CH.sub.2                               F    CH   imidazol-1-yl     1192 2     H         CH.sub.2                               F    CH   morpholin-1-yl     1193 2     H         CH.sub.2                               F    CH   2-methylimidazol-1-yl     1194 2     H         CH.sub.2                               F    CH   pyridin-3-yl     1195 2     H         CH.sub.2                               F    CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1196 2     H         CH.sub.2                               F    CH   pyrazol-1-yl     1197 2     H         CH.sub.2                               F    CH   phenyl     1198 2     H         CH.sub.2                               F    CH   cyclohexyl     1199 2     H         CH.sub.2                               F    CH   N,N-dimethylsulfamido     1200 2     H         CH.sub.2                               F    CH   N,N-dimethylamido     1201 2     H         CH.sub.2                               Cl   CH   imidazol-1-yl     1202 2     H         CH.sub.2                               Cl   CH   morpholin-1-yl     1203 2     H         CH.sub.2                               Cl   CH   2-methylimidazol-1-yl     1204 2     H         CH.sub.2                               Cl   CH   pyridin-3-yl     1205 2     H         CH.sub.2                               Cl   CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1206 2     H         CH.sub.2                               Cl   CH   pyrazol-1-yl     1207 2     H         CH.sub.2                               Cl   CH   phenyl     1208 2     H         CH.sub.2                               Cl   CH   cyclohexyl     1209 2     H         CH.sub.2                               Cl   CH   N,N-dimethylsulfamido     1210 2     H         CH.sub.2                               Cl   CH   N,N-dimethylamido     1211 2     H         CH.sub.2                               Br   CH   imidazol-1-yl     1212 2     H         CH.sub.2                               Br   CH   morpholin-1-yl     1213 2     H         CH.sub.2                               Br   CH   2-methylimidazol-1-yl     1214 2     H         CH.sub.2                               Br   CH   pyrazol-1-yl     1215 2     H         CH.sub.2                               Br   CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1216 2     H         CH.sub.2                               Br   CH   pyrazol-1-yl     1217 2     H         CH.sub.2                               Br   CH   phenyl     1218 2     H         CH.sub.2                               Br   CH   cyclohexyl     1219 2     H         CH.sub.2                               Br   CH   N,N-dimethylsulfamido     1220 2     H         CH.sub.2                               Br   CH   N,N-dimethylamido     1221 2     OH        bond F    CH   pyrazol-1-yl     1222 2     OH        bond F    CH   phenyl     1223 2     OH        bond F    CH   cyclohexyl     1224 2     OH        bond F    CH   N,N-dimethylsulfamido     1225 2     OH        bond F    CH   N,N-dimethylamido     1226 2     NHC(O)CH.sub.3                          bond Cl   CH   imidazol-1-yl     1227 2     NHC(O)CH.sub.3                          bond Cl   CH   morpholin-1-yl     1228 2     NHC(O)CH.sub.3                          bond Cl   CH   2-methylimidazol-1-yl     1229 2     NHC(O)CH.sub.3                          bond Cl   CH   pyridin-3-yl     1230 2     NHC(O)CH.sub.3                          bond Cl   CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1231 2     NHSO.sub.2 CH.sub.3                          bond Cl   CH   pyrazol-1-yl     1232 2     NHSO.sub.2 CH.sub.3                          bond Cl   CH   phenyl     1233 2     NHSO.sub.2 CH.sub.3                          bond Cl   CH   cyclohexyl     1234 2     NHSO.sub.2 CH.sub.3                          bond Cl   CH   N,N-dimethylsulfamido     1235 2     NHSO.sub.2 CH.sub.3                          bond Cl   CH   N,N-dimethylamido     1236 2     OCH.sub.3 bond Br   CH   imidazol-1-yl     1237 2     OCH.sub.3 bond Br   CH   morpholin-1-yl     1238 2     OCH.sub.3 bond Br   CH   2-methylimidazol-1-yl     1239 2     OCH.sub.3 bond Br   CH   pyridin-3-yl     1240 2     OCH.sub.3 bond Br   CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1241 2     OCH.sub.2 C.sub.6 H.sub.5                          bond Br   CH   pyrazol-1-yl     1242 2     OCH.sub.2 C.sub.6 H.sub.5                          bond Br   CH   phenyl     1243 2     OCH.sub.2 C.sub.6 H.sub.5                          bond Br   CH   cyclohexyl     1244 2     OCH.sub.2 C.sub.6 H.sub.5                          bond Br   CH   N,N-dimethylsulfamido     1245 2     OCH.sub.2 C.sub.6 H.sub.5                          bond Br   CH   N,N-dimethylamido     1246 2     OH        CH.sub.2                               CH   CH   pyrazol-1-yl     1247 2     OH        CH.sub.2                               CH   CH   phenyl     1248 2     OH        CH.sub.2                               CH   CH   cyclohexyl     1249 2     OH        CH.sub.2                               CH   CH   N,N-dimethylsulfamido     1250 2     OH        CH.sub.2                               CH   CH   N,N-dimethylamido     1251 2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   imidazol-1-yl     1252 2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   morpholin-1-yl     1253 2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   2-methylimidazol-1-yl     1254 2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   pyridin-3-yl     1255 2     NHC(O)CH.sub.3                          CH.sub.2                               N    CH   2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1256 2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   pyrazol-1-yl     1257 2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   phenyl     1258 2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   cyclohexyl     1259 2     NHSO.sub.2 CH3                          CH.sub.2                               N    CH   N,N-dimethylsulfamido     1260 2     NHSO.sub.2 CH.sub.3                          CH.sub.2                               N    CH   N,N-dimethylamido     1261 2     OCH.sub.3 CH.sub.2                               N    N    imidazol-1-yl     1262 2     OCH.sub.3 CH.sub.2                               N    N    morpholin-1-yl     1263 2     OCH.sub.3 CH.sub.2                               N    N    2-methylimidazol-1-yl     1264 2     OCH.sub.3 CH.sub.2                               N    N    pyridin-3-yl     1265 2     OCH.sub.3 CH.sub.2                               N    N    2-(5'-trifluoromethyl)                                         tetrazol-1'-yl     1266 2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    pyrazol-1-yl     1267 2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    phenyl     1268 2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    cyclohexyl     1269 2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    N,N-dimethylsulfamido     1270 2     OCH.sub.2 C.sub.6 H.sub.5                          CH.sub.2                               N    N    N,N-dimethylamido     ______________________________________

                  TABLE 14     ______________________________________     2 #STR35##     Ex.   n      R.sup.2    B     ______________________________________     1301  2      H          benzoyl     1302  2      H          phenylacetyl     1303  2      H          phenylsulfonyl     1304  2      H          benzylsulfonyl     1305  2      H          picolin-2-ylsulfonyl     1306  2      H          pyridin-2-ylsulfonyl     1307  2      H          picolin-2-yl     1308  2      H          (phenyl-N-methylamino)sulfonyl     1309  2      H          (1,1-dimethyl-1-phenyl)methylsulfonyl     1310  2      H          thiophen-2-ylmethyl     1311  2      OH         benzoyl     1312  2      OH         phenylacetyl     1313  2      OH         (phenyl-N-methylamino)sulfonyl     1314  2      OH         (1,1-dimethyl-1-phenyl)methylsulfonyl     1315  2      OH         picolin-2-ylsulfonyl     1316  2      OH         pyridin-2-ylsulfonyl     1317  2      OH         picolin-2-yl     1318  2      OH         thiophen-2-ylsulfonyl     1319  2      OH         thiophen-2-ylmethylsulfonyl     1320  2      OH         thiophen-2-ylmethyl     1321  2      NHC(O)CH.sub.3                             (phenyl-N-methylamino)sulfonyl     1322  2      NHC(O)CH.sub.3                             (1,1-dimethyl-1-phenyl)methylsulfonyl     1323  2      NHC(O)CH.sub.3                             phenylsulfonyl     1324  2      NHC(O)CH.sub.3                             benzylsulfonyl     1325  2      NHC(O)CH.sub.3                             picolin-2-ylsulfonyl     1326  2      NHC(O)CH.sub.3                             pyridin-2-ylsulfonyl     1327  2      NHC(O)CH.sub.3                             picolin-2-yl     1328  2      NHC(O)CH.sub.3                             thiophen-2-ylsulfonyl     1329  2      NHC(O)CH.sub.3                             thiophen-2-ylmethylsulfonyl     1330  2      NHC(O)CH.sub.3                             thiophen-2-ylmethyl     1331  2      NHSO.sub.2 CH.sub.3                             benzoyl     1332  2      NHSO.sub.2 CH.sub.3                             phenylacetyl     1333  2      NHSO.sub.2 CH.sub.3                             phenylsulfonyl     1334  2      NHSO.sub.2 CH.sub.3                             benzylsulfonyl     1335  2      NHSO.sub.2 CH.sub.3                             (phenyl-N-methylamino)sulfonyl     1336  2      NHSO.sub.2 CH.sub.3                             (1,1-dimethyl-1-phenyl)methylsulfonyl     1337  2      NHSO.sub.2 CH.sub.3                             picolin-2-yl     1338  2      NHSO.sub.2 CH.sub.3                             thiophen-2-ylsulfonyl     1339  2      NHSO.sub.2 CH.sub.3                             thiophen-2-ylmethylsulfonyl     1340  2      NHSO.sub.2 CH.sub.3                             thiophen-2-ylmethyl     ______________________________________

                  TABLE 15     ______________________________________     3 #STR36##     Ex.  n     R.sup.2   Z    B     ______________________________________     1401 2     H         bond benzoyl     1402 2     H         bond phenylacetyl     1403 2     H         bond phenylsulfonyl     1404 2     H         bond benzylsulfonyl     1405 2     H         bond picolin-2-ylsulfonyl     1406 2     H         bond pyridin-2-ylsulfonyl     1407 2     H         bond picolin-2-yl     1408 2     H         bond (phenyl-N-methylamino)sulfonyl     1409 2     H         bond (1,1-dimethyl-1-phenyl)methylsulfonyl     1410 2     H         bond thiophen-2-ylmethyl     1411 2     OH        bond benzoyl     1412 2     OH        bond phenylacetyl     1413 2     OH        bond (phenyl-N-methylamino)sulfonyl     1414 2     OH        bond (1,1-dimethyl-1-phenyl)methylsulfonyl     1415 2     OH        bond picolin-2-ylsulfonyl     1416 2     OH        bond pyridin-2-ylsulfonyl     1417 2     OH        bond picolin-2-yl     1418 2     OH        bond thiophen-2-ylsulfonyl     1419 2     OH        bond thiophen-2-ylmethylsulfonyl     1420 2     OH        bond thiophen-2-ylmethyl     1421 2     NHC(O)CH.sub.3                          bond (phenyl-N-methylamino)sulfonyl     1422 2     NHC(O)CH.sub.3                          bond (1,1-dimethyl-1-phenyl)methylsulfonyl     1423 2     NHC(O)CH.sub.3                          bond phenylsulfonyl     1424 2     NHC(O)CH.sub.3                          bond benzylsulfonyl     1425 2     NHC(O)CH.sub.3                          bond picolin-2-ylsulfonyl     1426 2     NHC(O)CH.sub.3                          bond pyridin-2-ylsulfonyl     1427 2     NHC(O)CH.sub.3                          bond picolin-2-yl     1428 2     NHC(O)CH.sub.3                          bond thiophen-2-ylsulfonyl     1429 2     NHC(O)CH.sub.3                          bond thiophen-2-ylmethylsulfonyl     1430 2     NHC(O)CH.sub.3                          bond thiophen-2-ylmethyl     1431 2     NHSO.sub.2 CH.sub.3                          bond benzoyl     1432 2     NHSO.sub.2 CH.sub.3                          bond phenylacetyl     1433 2     NHSO.sub.2 CH.sub.3                          bond phenylsulfonyl     1434 2     NHSO.sub.2 CH.sub.3                          bond benzylsulfonyl     1435 2     NHSO.sub.2 CH.sub.3                          bond (phenyl-N-methylamino)sulfonyl     1436 2     NHSO.sub.2 CH.sub.3                          bond (1,1-dimethyl-1-phenyl)methylsulfonyl     1437 2     NHSO.sub.2 CH.sub.3                          bond picolin-2-yl     1438 2     NHSO.sub.2 CH.sub.3                          bond thiophen-2-ylsulfonyl     1439 2     NHSO.sub.2 CH.sub.3                          bond thiophen-2-ylmethylsulfonyl     1440 2     NHSO.sub.2 CH.sub.3                          bond thiophen-2-ylmethyl     ______________________________________

                  TABLE 16     ______________________________________     4 #STR37##     Ex.  n     R.sup.2   Z    B     ______________________________________     1501 2     H         bond benzoyl     1502 2     H         bond phenylacetyl     1503 2     H         bond phenylsulfonyl     1504 2     H         bond benzylsulfonyl     1505 2     H         bond picolin-2-ylsulfonyl     1506 2     H         bond pyridin-2-ylsulfonyl     1507 2     H         bond picolin-2-yl     1508 2     H         bond (phenyl-N-methylamino)sulfonyl     1509 2     H         bond (1,1-dimethyl-1-phenyl)methylsulfonyl     1510 2     H         bond thiophen-2-ylmethyl     1511 2     OH        bond benzoyl     1512 2     OH        bond phenylacetyl     1513 2     OH        bond (phenyl-N-methylamino)sulfonyl     1514 2     OH        bond (1,1-dimethyl-1-phenyl)methylsulfonyl     1515 2     OH        bond picolin-2-ylsulfonyl     1516 2     OH        bond pyridin-2-ylsulfonyl     1517 2     OH        bond picolin-2-yl     1518 2     OH        bond thiophen-2-ylsulfonyl     1519 2     OH        bond thiophen-2-ylmethylsulfonyl     1520 2     OH        bond thiophen-2-ylmethyl     1521 2     NHC(O)CH.sub.3                          bond (phenyl-N-methylamino)sulfonyl     1522 2     NHC(O)CH.sub.3                          bond (1,1-dimethyl-1-phenyl)methylsulfonyl     1523 2     NHC(O)CH.sub.3                          bond phenylsulfonyl     1524 2     NHC(O)CH.sub.3                          bond benzylsulfonyl     1525 2     NHC(O)CH.sub.3                          bond picolin-2-ylsulfonyl     1526 2     NHC(O)CH.sub.3                          bond pyridin-2-ylsulfonyl     1527 2     NHC(O)CH.sub.3                          bond picolin-2-yl     1528 2     NHC(O)CH.sub.3                          bond thiophen-2-ylsulfonyl     1529 2     NHC(O)CH.sub.3                          bond thiophen-2-ylmethylsulfonyl     1530 2     NHC(O)CH.sub.3                          bond thiophen-2-ylmethyl     1531 2     NHSO.sub.2 CH.sub.3                          bond benzoyl     1532 2     NHSO.sub.2 CH.sub.3                          bond phenylacetyl     1533 2     NHSO.sub.2 CH.sub.3                          bond phenylsulfonyl     1534 2     NHSO.sub.2 CH.sub.3                          bond benzylsulfonyl     1535 2     NHSO.sub.2 CH.sub.3                          bond (phenyl-N-methylamino)sulfonyl     1536 2     NHSO.sub.2 CH.sub.3                          bond (1,1-dimethyl-1-phenyl)methylsulfonyl     1537 2     NHSO.sub.2 CH.sub.3                          bond picolin-2-yl     1538 2     NHSO.sub.2 CH.sub.3                          bond thiophen-2-ylsulfonyl     1539 2     NHSO.sub.2 CH.sub.3                          bond thiophen-2-ylmethylsulfonyl     1540 2     NHSO.sub.2 CH.sub.3                          bond thiophen-2-ylmethyl     ______________________________________

                  TABLE 17     ______________________________________     5 #STR38##     Ex.  n     R.sup.2     Z    B     ______________________________________     1601 2     H           bond picolin-2-ylsulfonyl     1602 2     H           bond pyridin-2-ylsulfonyl     1603 2     H           bond picolin-2-yl     1604 2     H           bond thiophen-2-ylsulfonyl     1605 2     H           bond thiophen-2-ylmethylsulfonyl     1606 2     H           bond thiophen-2-ylmethyl     1607 2     H           bond 4-fluorophenylsulfonyl     1608 2     H           bond 4-fluorobenzylsulfonyl     1609 2     H           bond phenylsulfonyl     1610 2     H           bond benzylsulfonyl     1611 2     H           bond (phenyl-N-methylamino)sulfonyl     1612 2     H           bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1613 2     OH          bond picolin-2-ylsulfonyl     1614 2     OH          bond pyridin-2-ylsulfonyl     1615 2     OH          bond picolin-2-yl     1616 2     OH          bond thiophen-2-ylsulfonyl     1617 2     OH          bond thiophen-2-ylmethylsulfonyl     1618 2     OH          bond thiophen-2-ylmethyl     1619 2     OH          bond 4-fluorophenylsulfonyl     1620 2     OH          bond 4-fluorobenzylsulfonyl     1621 2     OH          bond (phenyl-N-methylamino)sulfonyl     1622 2     OH          bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1623 2     OCH.sub.3   bond picolin-2-ylsulfonyl     1624 2     OCH.sub.3   bond pyridin-2-ylsulfonyl     1625 2     OCH.sub.3   bond picolin-2-yl     1626 2     OCH.sub.3   bond thiophen-2-ylsulfonyl     1627 2     OCH.sub.3   bond thiophen-2-ylmethylsulfonyl     1628 2     OCH.sub.3   bond thiophen-2-ylmethyl     1629 2     OCH.sub.3   bond (phenyl-N-methylamino)sulfonyl     1630 2     OCH.sub.3   bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1631 2     OCH.sub.3   bond phenylsulfonyl     1632 2     OCH.sub.3   bond benzylsulfonyl     1633 2     OCH.sub.2 C.sub.6 H.sub.5                            bond picolin-2-ylsulfonyl     1634 2     OCH.sub.2 C.sub.6 H.sub.5                            bond pyridin-2-ylsulfonyl     1635 2     OCH.sub.2 C.sub.6 H.sub.5                            bond picolin-2-yl     1636 2     OCH.sub.2 C.sub.6 H.sub.5                            bond thiophen-2-ylsulfonyl     1637 2     OCH.sub.2 C.sub.6 H.sub.5                            bond (phenyl-N-methylamino)sulfonyl     1638 2     OCH.sub.2 C.sub.6 H.sub.5                            bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1639 2     OCH.sub.2 C.sub.6 H.sub.5                            bond 4-fluorophenylsulfonyl     1640 2     OCH.sub.2 C.sub.6 H.sub.5                            bond 4-fluorobenzylsulfonyl     1641 2     OCH.sub.2 C.sub.6 H.sub.5                            bond phenylsulfonyl     1642 2     OCH.sub.2 C.sub.6 H.sub.5                            bond benzylsulfonyl     1643 2     NHC(O)CH.sub.3                            bond picolin-2-ylsulfonyl     1644 2     NHC(O)CH.sub.3                            bond pyridin-2-ylsulfonyl     1645 2     NHC(O)CH.sub.3                            bond (phenyl-N-methylamino)sulfonyl     1646 2     NHC(O)CH.sub.3                            bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1647 2     NHC(O)CH.sub.3                            bond thiophen-2-ylmethylsulfonyl     1648 2     NHC(O)CH.sub.3                            bond thiophen-2-ylmethyl     1649 2     NHC(O)CH.sub.3                            bond 4-fluorophenylsulfonyl     1650 2     NHC(O)CH.sub.3                            bond 4-fluorobenzylsulfonyl     1651 2     NHC(O)CH.sub.3                            bond phenylsulfonyl     1652 2     NHC(O)CH.sub.3                            bond benzylsulfonyl     1653 2     NHC(O)OCH.sub.3                            bond (phenyl-N-methylamino)sulfonyl     1654 2     NHC(O)OCH.sub.3                            bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1655 2     NHC(O)OCH.sub.3                            bond picolin-2-yl     1656 2     NHC(O)OCH.sub.3                            bond thiophen-2-ylsulfonyl     1657 2     NHC(O)OCH.sub.3                            bond thiophen-2-ylmethylsulfonyl     1658 2     NHC(O)OCH.sub.3                            bond thiophen-2-ylmethyl     1659 2     NHC(O)OCH.sub.3                            bond 4-fluorophenylsulfonyl     1660 2     NHC(O)OCH.sub.3                            bond 4-fluorobenzylsulfonyl     1661 2     NHC(O)OCH.sub.3                            bond phenylsulfonyl     1662 2     NHC(O)OCH.sub.3                            bond benzylsulfonyl     1663 2     NHC(O)NHCH.sub.3                            bond picolin-2-ylsulfonyl     1664 2     NHC(O)NHCH.sub.3                            bond pyridin-2-ylsulfonyl     1665 2     NHC(O)NHCH.sub.3                            bond picolin-2-yl     1666 2     NHC(O)NHCH.sub.3                            bond thiophen-2-ylsulfonyl     1667 2     NHC(O)NHCH.sub.3                            bond thiophen-2-ylmethylsulfonyl     1668 2     NHC(O)NHCH.sub.3                            bond thiophen-2-ylmethyl     1669 2     NHC(O)NHCH.sub.3                            bond 4-fluorophenylsulfonyl     1670 2     NHC(O)NHCH.sub.3                            bond 4-fluorobenzylsulfonyl     1671 2     NHC(O)NHCH.sub.3                            bond (phenyl-N-methylamino)sulfonyl     1672 2     NHC(O)NHCH.sub.3                            bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1673 2     NHC(O)C.sub.6 H.sub.5                            bond picolin-2-ylsulfonyl     1674 2     NHC(O)C.sub.6 H.sub.5                            bond pyridin-2-ylsulfonyl     1675 2     NHC(O)C.sub.6 H.sub.5                            bond picolin-2-yl     1676 2     NHC(O)C.sub.6 H.sub.5                            bond thiophen-2-ylsulfonyl     1677 2     NHC(O)C.sub.6 H.sub.5                            bond thiophen-2-ylmethylsulfonyl     1678 2     NHC(O)C.sub.6 H.sub.5                            bond thiophen-2-ylmethyl     1679 2     NHC(O)C.sub.6 H.sub.5                            bond (phenyl-N-methylamino)sulfonyl     1680 2     NHC(O)C.sub.6 H.sub.5                            bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1681 2     NHC(O)C.sub.6 H.sub.5                            bond phenylsulfonyl     1682 2     NHC(O)C.sub.6 H.sub.5                            bond benzylsulfonyl     1683 2     NHSO.sub.2 CH.sub.3                            bond picolin-2-ylsulfonyl     1684 2     NHSO.sub.2 CH.sub.3                            bond pyridin-2-ylsulfonyl     1685 2     NHSO.sub.2 CH.sub.3                            bond picolin-2-yl     1686 2     NHSO.sub.2 CH.sub.3                            bond thiophen-2-ylsulfonyl     1687 2     NHSO.sub.2 CH.sub.3                            bond (phenyl-N-methylamino)sulfonyl     1688 2     NHSO.sub.2 CH.sub.3                            bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1689 2     NHSO.sub.2 CH.sub.3                            bond 4-fluorophenylsulfonyl     1690 2     NHSO.sub.2 CH.sub.3                            bond 4-fluorobenzylsulfonyl     1691 2     NHSO.sub.2 CH.sub.3                            bond phenylsulfonyl     1692 2     NHSO.sub.2 CH.sub.3                            bond benzylsulfonyl     1693 2     NHSO.sub.2 NHCH.sub.3                            bond picolin-2-ylsulfonyl     1694 2     NHSO.sub.2 NHCH.sub.3                            bond pyridin-2-ylsulfonyl     1695 2     NHSO.sub.2 NHCH.sub.3                            bond (phenyl-N-methylamino)sulfonyl     1696 2     NHSO.sub.2 NHCH.sub.3                            bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1697 2     NHSO.sub.2 NHCH.sub.3                            bond thiophen-2-ylmethylsulfonyl     1698 2     NHSO.sub.2 NHCH.sub.3                            bond thiophen-2-ylmethyl     1699 2     NHSO.sub.2 NHCH.sub.3                            bond 4-fluorophenylsulfonyl     1700 2     NHSO.sub.2 NHCH.sub.3                            bond 4-fluorobenzylsulfonyl     1701 2     NHSO.sub.2 NHCH.sub.3                            bond phenylsulfonyl     1702 2     NHSO.sub.2 NHCH.sub.3                            bond benzylsulfonyl     1703 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond (phenyl-N-methylamino)sulfonyl     1704 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond (1,1-dimethyl-1-phenyl)methyl- sulfonyl     1705 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond picolin-2-yl     1706 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond thiophen-2-ylsulfonyl     1707 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond thiophen-2-ylmethylsulfonyl     1708 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond thiophen-2-ylmethyl     1709 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond 4-fluorophenylsulfonyl     1710 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond 4-fluorobenzylsulfonyl     1711 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond phenylsulfonyl     1712 2     NHSO.sub.2 C.sub.6 H.sub.5                            bond benzylsulfonyl     ______________________________________

                  TABLE 18     ______________________________________     1 #STR39##     Ex.  n      R.sup.2     Z     B     ______________________________________     1801 2      H           CH.sub.2                                   picolin-2-ylsulfonyl     1802 2      H           CH.sub.2                                   pyridin-2-ylsulfonyl     1803 2      H           CH.sub.2                                   picolin-2-yl     1804 2      H           CH.sub.2                                   thiophen-2-ylsulfonyl     1805 2      H           CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1806 2      H           CH.sub.2                                   thiophen-2-ylmethyl     1807 2      H           CH.sub.2                                   4-fluorophenylsulfonyl     1808 2      H           CH.sub.2                                   4-fluorobenzylsulfonyl     1809 2      H           CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1810 2      H           CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1811 2      OH          CH.sub.2                                   picolin-2-ylsulfonyl     1812 2      OH          CH.sub.2                                   pyridin-2-ylsulfonyl     1813 2      OH          CH.sub.2                                   picolin-2-yl     1814 2      OH          CH.sub.2                                   thiophen-2-ylsulfonyl     1815 2      OH          CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1816 2      OH          CH.sub.2                                   thiophen-2-ylmethyl     1817 2      OH          CH.sub.2                                   4-fluorophenylsulfonyl     1818 2      OH          CH.sub.2                                   4-fluorobenzylsulfonyl     1819 2      OH          CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1820 2      OH          CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1821 2      OCH.sub.3   CH.sub.2                                   picolin-2-ylsulfonyl     1822 2      OCH.sub.3   CH.sub.2                                   pyridin-2-ylsulfonyl     1823 2      OCH.sub.3   CH.sub.2                                   picolin-2-yl     1824 2      OCH.sub.3   CH.sub.2                                   thiophen-2-ylsulfonyl     1825 2      OCH.sub.3   CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1826 2      OCH.sub.3   CH.sub.2                                   thiophen-2-ylmethyl     1827 2      OCH.sub.3   CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1828 2      OCH.sub.3   CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1829 2      OCH.sub.3   CH.sub.2                                   phenylsulfonyl     1830 2      OCH.sub.3   CH.sub.2                                   benzylsulfonyl     1831 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   picolin-2-ylsulfonyl     1832 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   pyridin-2-ylsulfonyl     1833 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   picolin-2-yl     1834 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   thiophen-2-ylsulfonyl     1835 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1836 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1837 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   4-fluorophenylsulfonyl     1838 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   4-fluorobenzylsulfonyl     1839 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   phenylsulfonyl     1840 2      OCH.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   benzylsulfonyl     1841 2      NHC(O)CH.sub.3                             CH.sub.2                                   picolin-2-ylsulfonyl     1842 2      NHC(O)CH.sub.3                             CH.sub.2                                   pyridin-2-ylsulfonyl     1843 2      NHC(O)CH.sub.3                             CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1844 2      NHC(O)CH.sub.3                             CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1845 2      NHC(O)CH.sub.3                             CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1846 2      NHC(O)CH.sub.3                             CH.sub.2                                   thiophen-2-ylmethyl     1847 2      NHC(O)CH.sub.3                             CH.sub.2                                   4-fluorophenylsulfonyl     1848 2      NHC(O)CH.sub.3                             CH.sub.2                                   4-fluorobenzylsulfonyl     1849 2      NHC(O)CH.sub.3                             CH.sub.2                                   phenylsulfonyl     1850 2      NHC(O)CH.sub.3                             CH.sub.2                                   benzylsulfonyl     1851 2      NHC(O)OCH.sub.3                             CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1852 2      NHC(O)OCH.sub.3                             CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1853 2      NHC(O)OCH.sub.3                             CH.sub.2                                   picolin-2-yl     1854 2      NHC(O)OCH.sub.3                             CH.sub.2                                   thiophen-2-ylsulfonyl     1855 2      NHC(O)OCH.sub.3                             CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1856 2      NHC(O)OCH.sub.3                             CH.sub.2                                   thiophen-2-ylmethyl     1857 2      NHC(O)OCH.sub.3                             CH.sub.2                                   4-fluorophenylsulfonyl     1858 2      NHC(O)OCH.sub.3                             CH.sub.2                                   4-fluorobenzylsulfonyl     1859 2      NHC(O)OCH.sub.3                             CH.sub.2                                   phenylsulfonyl     1860 2      NHC(O)OCH.sub.3                             CH.sub.2                                   benzylsulfonyl     1861 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   picolin-2-ylsulfonyl     1862 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   pyridin-2-ylsulfonyl     1863 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   picolin-2-yl     1864 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   thiophen-2-ylsulfonyl     1865 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1866 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   thiophen-2-ylmethyl     1867 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   4-fluorophenylsulfonyl     1868 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   4-fluorobenzylsulfonyl     1869 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1870 2      NHC(O)NHCH.sub.3                             CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1871 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   picolin-2-ylsulfonyl     1872 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   pyridin-2-ylsulfonyl     1873 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   picolin-2-yl     1874 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   thiophen-2-ylsulfonyl     1875 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1876 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   thiophen-2-ylmethyl     1877 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1878 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1879 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   phenylsulfonyl     1880 2      NHC(O)C.sub.6 H.sub.5                             CH.sub.2                                   benzylsulfonyl     1881 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   picolin-2-ylsulfonyl     1882 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   pyridin-2-ylsulfonyl     1883 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   picolin-2-yl     1884 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   thiophen-2-ylsulfonyl     1885 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1886 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1887 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   4-fluorophenylsulfonyl     1888 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   4-fluorobenzylsulfonyl     1889 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   phenylsulfonyl     1890 2      NHSO.sub.2 CH.sub.3                             CH.sub.2                                   benzylsulfonyl     1891 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   picolin-2-ylsulfonyl     1892 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   pyridin-2-ylsulfonyl     1893 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1894 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1895 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1896 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   thiophen-2-ylmethyl     1897 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   4-fluorophenylsulfonyl     1898 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   4-fluorobenzylsulfonyl     1899 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   phenylsulfonyl     1900 2      NHSO.sub.2 NHCH.sub.3                             CH.sub.2                                   benzylsulfonyl     1901 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   (phenyl-N-                                   methylamino)sulfonyl     1902 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   (1,1-dimethyl-1-                                   phenyl)methylsulfonyl     1903 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   picolin-2-yl     1904 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   thiophen-2-ylsulfonyl     1905 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   thiophen-2-ylmethylsulfonyl     1906 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   thiophen-2-ylmethyl     1907 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   4-fluorophenylsulfonyl     1908 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   4-fluorobenzylsulfonyl     1909 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   phenylsulfonyl     1910 2      NHSO.sub.2 C.sub.6 H.sub.5                             CH.sub.2                                   benzylsulfonyl     ______________________________________

                  TABLE 19     ______________________________________     2 #STR40##     Ex.  n     R.sup.2                      Z            A*    B*     ______________________________________     2001 0     H     (CH.sub.2).sub.2 O                                   phenyl                                         amino     2002 0     H     (CH.sub.2).sub.2 O                                   phenyl                                         amidino     2003 0     H     (CH.sub.2).sub.2 O                                   phenyl                                         guanidino     2004 0     H     (CH.sub.2).sub.2 O                                   phenyl                                         benzyl     2005 0     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         phenyl     2006 0     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         cyclohexyl     2007 0     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         4-pyridyl     2008 0     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         2-furanyl     2009 0     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         piperidinyl     2010 0     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         phenethyl     2011 0     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         phenylcarbonyl     2012 0     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         2-aminophenyl-                                         carbonyl     2013 0     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         benzylcarbonyl     2014 0     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         4-acetamidophenyl-                                         methanecarbonyl     2015 0     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         phenylsulfonyl     2016 0     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         4-amidinophenyl-                                         sulfonyl     2017 0     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         benzylsulfonyl     2018 0     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         4-methoxycarbonyl-                                         phenylmethane-                                         sulfonyl     2019 0     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         phenylsulfonamide     2020 0     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         4-acetamidophenyl-                                         sulfonamide     2021 0     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         phenylcarbamide     2022 0     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         2-aminophenyl-                                         carbamide     2023 0     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         benzylamine     2024 0     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         4-amidinophenyl-                                         methaneamine     2025 0     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         amino     2026 0     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         amidino     2027 0     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         guanidino     2028 0     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         benzyl     2029 0     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         phenyl     2030 0     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         cyclohexyl     2031 0     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         4-pyridyl     2032 0     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         2-furanyl     2033 0     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         piperidinyl     2034 0     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         phenethyl     2035 0     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         phenylcarbonyl     2036 0     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         2-aminophenyl-                                         carbonyl     2037 0     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         benzylcarbonyl     2038 0     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         4-acetamidophenyl-                                         methanecarbonyl     2039 0     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         phenylsulfonyl     2040 0     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         4-amidinophenyl-                                         sulfonyl     2041 0     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         benzylsulfonyl     2042 0     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         4-methoxycarbonyl-                                         phenylmethane-                                         sulfonyl     2043 0     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         phenylsulfonamide     2044 0     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         4-acetamidophenyl-                                         sulfonamide     2045 0     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         phenylcarbamide     2046 0     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         2-aminophenyl-                                         carbamide     2047 0     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         benzylamine     2048 0     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         4-amidinophenyl-                                         methaneamine     ______________________________________      *B is substituted para to Z on A.

                  TABLE 20     ______________________________________     3 #STR41##     Ex.  n     R.sup.2                      Z            A*    B*     ______________________________________     2101 1     H     (CH.sub.2).sub.2 O                                   phenyl                                         amino     2102 1     H     (CH.sub.2).sub.2 O                                   phenyl                                         amidino     2103 1     H     (CH.sub.2).sub.2 O                                   phenyl                                         guanidino     2104 1     H     (CH.sub.2).sub.2 O                                   phenyl                                         benzyl     2105 1     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         phenyl     2106 1     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         cyclohexyl     2107 1     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         4-pyridyl     2108 1     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         2-furanyl     2109 1     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         piperidinyl     2110 1     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         phenethyl     2111 1     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         phenylcarbonyl     2112 1     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         2-aminophenyl-                                         carbonyl     2113 1     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         benzylcarbonyl     2114 1     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         4-acetamidophenyl-                                         methanecarbonyl     2115 1     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         phenylsulfonyl     2116 1     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         4-amidinophenyl-                                         sulfonyl     2117 1     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         benzylsulfonyl     2118 1     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         4-methoxycarbonyl-                                         phenylmethane-                                         sulfonyl     2119 1     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         phenylsulfonamide     2120 1     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         4-acetamidophenyl-                                         sulfonamide     2121 1     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         phenylcarbamide     2122 1     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         2-aminophenyl-                                         carbamide     2123 1     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         benzylamine     2124 1     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         4-amidinophenyl-                                         methaneamine     2125 1     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         amino     2126 1     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         amidino     2127 1     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         guanidino     2128 1     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         benzyl     2129 1     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         phenyl     2130 1     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         cyclohexyl     2131 1     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         4-pyridyl     2132 1     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         2-furanyl     2133 1     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         piperidinyl     2134 1     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         phenethyl     2135 1     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         phenylcarbonyl     2136 1     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         2-aminophenyl-                                         carbonyl     2137 1     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         benzylcarbonyl     2138 1     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         4-acetamidophenyl-                                         methanecarbonyl     2139 1     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         phenylsulfonyl     2140 1     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         4-amidinophenyl-                                         sulfonyl     2141 1     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         benzylsulfonyl     2142 1     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         4-methoxycarbonyl-                                         phenylmethane-                                         sulfonyl     2143 1     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         phenylsulfonamide     2144 1     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         4-acetamidophenyl-                                         sulfonamide     2145 1     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         phenylcarbamide     2146 1     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         2-aminophenyl-                                         carbamide     2147 1     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         benzylamine     2148 1     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         4-amidinophenyl-                                         methaneamine     ______________________________________      *B is substituted para to Z on A.

                  TABLE 21     ______________________________________     4 #STR42##     Ex.  n     R.sup.2                      Z            A*    B*     ______________________________________     2201 2     H     (CH.sub.2).sub.2 O                                   phenyl                                         amino     2202 2     H     (CH.sub.2).sub.2 O                                   phenyl                                         amidino     2203 2     H     (CH.sub.2).sub.2 O                                   phenyl                                         guanidino     2204 2     H     (CH.sub.2).sub.2 O                                   phenyl                                         benzyl     2205 2     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         phenyl     2206 2     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         cyclohexyl     2207 2     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         4-pyridyl     2208 2     H     (CH.sub.2).sub.2 C(O)                                   phenyl                                         2-furanyl     2209 2     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         piperidinyl     2210 2     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         phenethyl     2211 2     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         phenylcarbonyl     2212 2     H     (CH.sub.2).sub.2 C(O)O                                   phenyl                                         2-aminophenyl-                                         carbonyl     2213 2     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         benzylcarbonyl     2214 2     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         4-acetamidophenyl-                                         methanecarbonyl     2215 2     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         phenylsulfonyl     2216 2     H     (CH.sub.2).sub.2 C(O)NH                                   phenyl                                         4-amidinophenyl-                                         sulfonyl     2217 2     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         benzylsulfonyl     2218 2     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         4-methoxycarbonyl-                                         phenylmethane-                                         sulfonyl     2219 2     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         phenylsulfonamide     2220 2     H     (CH.sub.2).sub.2 NHC(O)NH                                   phenyl                                         4-acetamidophenyl-                                         sulfonamide     2221 2     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         phenylcarbamide     2222 2     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         2-aminophenyl-                                         carbamide     2223 2     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         benzylamine     2224 2     H     (CH.sub.2).sub.2 S(O).sub.2 NH                                   phenyl                                         4-amidinophenyl-                                         methaneamine     2225 2     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         amino     2226 2     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         amidino     2227 2     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         guanidino     2228 2     H     (CH.sub.2).sub.2 OCH.sub.2                                   phenyl                                         benzyl     2229 2     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         phenyl     2230 2     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         cyclohexyl     2231 2     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         4-pyridyl     2232 2     H     (CH.sub.2).sub.2 C(O)CH.sub.2                                   phenyl                                         2-furanyl     2233 2     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         piperidinyl     2234 2     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         phenethyl     2235 2     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         phenylcarbonyl     2236 2     H     (CH.sub.2).sub.2 C(O)OCH.sub.2                                   phenyl                                         2-aminophenyl-                                         carbonyl     2237 2     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         benzylcarbonyl     2238 2     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         4-acetamidophenyl-                                         methanecarbonyl     2239 2     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         phenylsulfonyl     2240 2     H     (CH.sub.2).sub.2 C(O)NHCH.sub.2                                   phenyl                                         4-amidinophenyl-                                         sulfonyl     2241 2     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         benzylsulfonyl     2242 2     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         4-methoxycarbonyl-                                         phenylmethane-                                         sulfonyl     2243 2     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         phenylsulfonamide     2244 2     H     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                                   phenyl                                         4-acetamidophenyl-                                         sulfonamide     2245 2     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         phenylcarbamide     2246 2     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         2-aminophenyl-                                         carbamide     2247 2     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         benzylamine     2248 2     H     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                                   phenyl                                         4-amidinophenyl-                                         methaneamine     ______________________________________      *B is substituted para to Z on A.

                  TABLE 22     ______________________________________     5 #STR43##     Ex.  n     Z              A*       B*     ______________________________________     2301 0     (CH.sub.2).sub.2 O                               2-fluorophenyl                                        imidazol-1-yl     2302 0     (CH.sub.2).sub.2 O                               2-chlorophenyl                                        N,N-                                        dimethylamido     2303 0     (CH.sub.2).sub.2 O                               2-bromophenyl                                        morpholin-1-yl     2304 0     (CH.sub.2).sub.2 O                               2-pyridyl                                        2-methylindazol-                                        1-yl     2305 0     (CH.sub.2).sub.2 O                               2-pyrimidinyl                                        N,N-dimethyl-                                        sulfamido     2306 0     (CH.sub.2).sub.2 C(O)                               2-fluorophenyl                                        pyridin-3-yl     2307 0     (CH.sub.2).sub.2 C(O)                               2-chlorophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2308 0     (CH.sub.2).sub.2 C(O)                               2-bromophenyl                                        pyrazol-1-yl     2309 0     (CH.sub.2).sub.2 C(O)                               2-pyridyl                                        cyclohexyl     2310 0     (CH.sub.2).sub.2 C(O)O                               2-pyrimidinyl                                        imidazol-1-yl     2311 0     (CH.sub.2).sub.2 C(O)O                               2-fluorophenyl                                        N,N-                                        dimethylamido     2312 0     (CH.sub.2).sub.2 C(O)O                               2-chlorophenyl                                        morpholin-1-yl     2313 0     (CH.sub.2).sub.2 C(O)O                               2-bromophenyl                                        2-methylindazol-                                        1-yl     2314 0     (CH.sub.2).sub.2 C(O)NH                               2-pyridyl                                        N,N-dimethyl-                                        sulfamido     2315 0     (CH.sub.2).sub.2 C(O)NH                               2-pyrimidinyl                                        pyridin-3-yl     2316 0     (CH.sub.2).sub.2 C(O)NH                               2-fluorophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2317 0     (CH.sub.2).sub.2 C(O)NH                               2-chlorophenyl                                        pyrazol-1-yl     2318 0     (CH.sub.2).sub.2 C(O)NH                               2-bromophenyl                                        cyclohexyl     2319 0     (CH.sub.2).sub.2 NHC(O)NH                               2-pyridyl                                        imidazol-1-yl     2320 0     (CH.sub.2).sub.2 NHC(O)NH                               2-pyrimidinyl                                        N,N-                                        dimethylamido     2321 0     (CH.sub.2).sub.2 NHC(O)NH                               2-fluorophenyl                                        morpholin-1-yl     2322 0     (CH.sub.2).sub.2 NHC(O)NH                               2-chlorophenyl                                        2-methylindazol-                                        1-yl     2323 0     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-bromophenyl                                        N,N-dimethyl-                                        sulfamido     2324 0     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-pyridyl                                        pyridin-3-yl     2325 0     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-pyrimidinyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2326 0     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-fluorophenyl                                        pyrazol-1-yl     2327 0     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-chlorophenyl                                        cyclohexyl     2328 0     (CH.sub.2).sub.2 OCH.sub.2                               2-bromophenyl                                        imidazol-1-yl     2329 0     (CH.sub.2).sub.2 OCH.sub.2                               2-pyridyl                                        N,N-                                        dimethylamido     2330 0     (CH.sub.2).sub.2 OCH.sub.2                               2-pyrimidinyl                                        morpholin-1-yl     2331 0     (CH.sub.2).sub.2 OCH.sub.2                               2-fluorophenyl                                        2-methylindazol-                                        1-yl     2332 0     (CH.sub.2).sub.2 OCH.sub.2                               2-chlorophenyl                                        N,N-dimethyl-                                        sulfamido     2333 0     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-bromophenyl                                        pyridin-3-yl     2334 0     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-pyridyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2335 0     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-pyrimidinyl                                        pyrazol-1-yl     2336 0     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-fluorophenyl                                        cyclohexyl     2337 0     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-chlorophenyl                                        imidazol-1-yl     2338 0     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-bromophenyl                                        N,N-                                        dimethylamido     2339 0     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-pyridyl                                        morpholin-1-yl     2340 0     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-pyrimidinyl                                        2-methylindazol-                                        1-yl     2341 0     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-fluorophenyl                                        N,N-dimethyl-                                        sulfamido     2342 0     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-chlorophenyl                                        pyridin-3-yl     2343 0     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-bromophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2344 0     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-pyridyl                                        pyrazol-1-yl     2345 0     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-pyrimidinyl                                        cyclohexyl     2346 0     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-fluorophenyl                                        imidazol-1-yl     2347 0     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-chlorophenyl                                        N,N-                                        dimethylamido     2348 0     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-bromophenyl                                        morpholin-1-yl     2349 0     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-pyridyl                                        2-methylindazol-                                        1-yl     2350 0     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-fluorophenyl                                        N,N-dimethyl-                                        sulfamido     2351 0     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-chlorophenyl                                        pyridin-3-yl     2352 0     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-bromophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2353 0     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-pyridyl                                        pyrazol-1-yl     2354 0     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-pyrimidinyl                                        cyclohexyl     ______________________________________      *B is substituted para to Z on A.

                  TABLE 23     ______________________________________     6 #STR44##     Ex.  n     Z              A*       B*     ______________________________________     2401 1     (CH.sub.2).sub.2 O                               2-fluorophenyl                                        imidazol-1-yl     2402 1     (CH.sub.2).sub.2 O                               2-chlorophenyl                                        N,N-                                        dimethylamido     2403 1     (CH.sub.2).sub.2 O                               2-bromophenyl                                        morpholin-1-yl     2404 1     (CH.sub.2).sub.2 O                               2-pyridyl                                        2-methylindazol-                                        1-yl     2405 1     (CH.sub.2).sub.2 O                               2-pyrimidinyl                                        N,N-dimethyl-                                        sulfamido     2406 1     (CH.sub.2).sub.2 C(O)                               2-fluorophenyl                                        pyridin-3-yl     2407 1     (CH.sub.2).sub.2 C(O)                               2-chlorophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2408 1     (CH.sub.2).sub.2 C(O)                               2-bromophenyl                                        pyrazol-1-yl     2409 1     (CH.sub.2).sub.2 C(O)                               2-pyridyl                                        cyclohexyl     2410 1     (CH.sub.2).sub.2 C(O)O                               2-pyrimidinyl                                        imidazol-1-yl     2411 1     (CH.sub.2).sub.2 C(O)O                               2-fluorophenyl                                        N,N-                                        dimethylamido     2412 1     (CH.sub.2).sub.2 C(O)O                               2-chlorophenyl                                        morpholin-1-yl     2413 1     (CH.sub.2).sub.2 C(O)O                               2-bromophenyl                                        2-methylindazol-                                        1-yl     2414 1     (CH.sub.2).sub.2 C(O)NH                               2-pyridyl                                        N,N-dimethyl-                                        sulfamido     2415 1     (CH.sub.2).sub.2 C(O)NH                               2-pyrimidinyl                                        pyridin-3-yl     2416 1     (CH.sub.2).sub.2 C(O)NH                               2-fluorophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2417 1     (CH.sub.2).sub.2 C(O)NH                               2-chlorophenyl                                        pyrazol-1-yl     2418 1     (CH.sub.2).sub.2 C(O)NH                               2-bromophenyl                                        cyclohexyl     2419 1     (CH.sub.2).sub.2 NHC(O)NH                               2-pyridyl                                        imidazol-1-yl     2420 1     (CH.sub.2).sub.2 NHC(O)NH                               2-pyrimidinyl                                        N,N-                                        dimethylamido     2421 1     (CH.sub.2).sub.2 NHC(O)NH                               2-fluorophenyl                                        morpholin-1-yl     2422 1     (CH.sub.2).sub.2 NHC(O)NH                               2-chlorophenyl                                        2-methylindazol-                                        1-yl     2423 1     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-bromophenyl                                        N,N-dimethyl-                                        sulfamido     2424 1     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-pyridyl                                        pyridin-3-yl     2425 1     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-pyrimidinyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2426 1     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-fluorophenyl                                        pyrazol-1-yl     2427 1     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-chlorophenyl                                        cyclohexyl     2428 1     (CH.sub.2).sub.2 OCH.sub.2                               2-bromophenyl                                        imidazol-1-yl     2429 1     (CH.sub.2).sub.2 OCH.sub.2                               2-pyridyl                                        N,N-                                        dimethylamido     2430 1     (CH.sub.2).sub.2 OCH.sub.2                               2-pyrimidinyl                                        morpholin-1-yl     2431 1     (CH.sub.2).sub.2 OCH.sub.2                               2-fluorophenyl                                        2-methylindazol-                                        1-yl     2432 1     (CH.sub.2).sub.2 OCH.sub.2                               2-chlorophenyl                                        N,N-dimethyl-                                        sulfamido     2433 1     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-bromophenyl                                        pyridin-3-yl     2434 1     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-pyridyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2435 1     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-pyrimidinyl                                        pyrazol-1-yl     2436 1     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-fluorophenyl                                        cyclohexyl     2437 1     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-chlorophenyl                                        imidazol-1-yl     2438 1     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-bromophenyl                                        N,N-                                        dimethylamido     2439 1     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-pyridyl                                        morpholin-1-yl     2440 1     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-pyrimidinyl                                        2-methylindazol-                                        1-yl     2441 1     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-fluorophenyl                                        N,N-dimethyl-                                        sulfamido     2442 1     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-chlorophenyl                                        pyridin-3-yl     2443 1     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-bromophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2444 1     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-pyridyl                                        pyrazol-1-yl     2445 1     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-pyrimidinyl                                        cyclohexyl     2446 1     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-fluorophenyl                                        imidazol-1-yl     2447 1     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-chlorophenyl                                        N,N-                                        dimethylamido     2448 1     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-bromophenyl                                        morpholin-1-yl     2449 1     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-pyridyl                                        2-methylindazol-                                        1-yl     2450 1     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-fluorophenyl                                        N,N-dimethyl-                                        sulfamido     2451 1     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-chlorophenyl                                        pyridin-3-yl     2452 1     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-bromophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2453 1     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-pyridyl                                        pyrazol-1-yl     2454 1     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-pyrimidinyl                                        cyclohexyl     ______________________________________      *B is substituted para to Z on A.

                  TABLE 24     ______________________________________     7 #STR45##     Ex.  n     Z              A*       B*     ______________________________________     2501 2     (CH.sub.2).sub.2 O                               2-fluorophenyl                                        imidazol-1-yl     2502 2     (CH.sub.2).sub.2 O                               2-chlorophenyl                                        N,N-                                        dimethylamido     2503 2     (CH.sub.2).sub.2 O                               2-bromophenyl                                        morpholin-1-yl     2504 2     (CH.sub.2).sub.2 O                               2-pyridyl                                        2-methylindazol-                                        1-yl     2505 2     (CH.sub.2).sub.2 O                               2-pyrimidinyl                                        N,N-dimethyl-                                        sulfamido     2506 2     (CH.sub.2).sub.2 C(O)                               2-fluorophenyl                                        pyridin-3-yl     2507 2     (CH.sub.2).sub.2 C(O)                               2-chlorophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2508 2     (CH.sub.2).sub.2 C(O)                               2-bromophenyl                                        pyrazol-1-yl     2509 2     (CH.sub.2).sub.2 C(O)                               2-pyridyl                                        cyclohexyl     2510 2     (CH.sub.2).sub.2 C(O)O                               2-pyrimidinyl                                        imidazol-1-yl     2511 2     (CH.sub.2).sub.2 C(O)O                               2-fluorophenyl                                        N,N-                                        dimethylamido     2512 2     (CH.sub.2).sub.2 C(O)O                               2-chlorophenyl                                        morpholin-1-yl     2513 2     (CH.sub.2).sub.2 C(O)O                               2-bromophenyl                                        2-methylindazol-                                        1-yl     2514 2     (CH.sub.2).sub.2 C(O)NH                               2-pyridyl                                        N,N-dimethyl-                                        sulfamido     2515 2     (CH.sub.2).sub.2 C(O)NH                               2-pyrimidinyl                                        pyridin-3-yl     2516 2     (CH.sub.2).sub.2 C(O)NH                               2-fluorophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2517 2     (CH.sub.2).sub.2 C(O)NH                               2-chlorophenyl                                        pyrazol-1-yl     2518 2     (CH.sub.2).sub.2 C(O)NH                               2-bromophenyl                                        cyclohexyl     2519 2     (CH.sub.2).sub.2 NHC(O)NH                               2-pyridyl                                        imidazol-1-yl     2520 2     (CH.sub.2).sub.2 NHC(O)NH                               2-pyrimidinyl                                        N,N-                                        dimethylamido     2521 2     (CH.sub.2).sub.2 NHC(O)NH                               2-fluorophenyl                                        morpholin-1-yl     2522 2     (CH.sub.2).sub.2 NHC(O)NH                               2-chlorophenyl                                        2-methylindazol-                                        1-yl     2523 2     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-bromophenyl                                        N,N-dimethyl-                                        sulfamido     2524 2     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-pyridyl                                        pyridin-3-yl     2525 2     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-pyrimidinyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2526 2     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-fluorophenyl                                        pyrazol-1-yl     2527 2     (CH.sub.2).sub.2 S(O).sub.2 NH                               2-chlorophenyl                                        cyclohexyl     2528 2     (CH.sub.2).sub.2 OCH.sub.2                               2-bromophenyl                                        imidazol-1-yl     2529 2     (CH.sub.2).sub.2 OCH.sub.2                               2-pyridyl                                        N,N-                                        dimethylamido     2530 2     (CH.sub.2).sub.2 OCH.sub.2                               2-pyrimidinyl                                        morpholin-1-yl     2531 2     (CH.sub.2).sub.2 OCH.sub.2                               2-fluorophenyl                                        2-methylindazol-                                        1-yl     2532 2     (CH.sub.2).sub.2 OCH.sub.2                               2-chlorophenyl                                        N,N-dimethyl-                                        sulfamido     2533 2     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-bromophenyl                                        pyridin-3-yl     2534 2     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-pyridyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2535 2     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-pyrimidinyl                                        pyrazol-1-yl     2536 2     (CH.sub.2).sub.2 C(O)CH.sub.2                               2-fluorophenyl                                        cyclohexyl     2537 2     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-chlorophenyl                                        imidazol-1-yl     2538 2     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-bromophenyl                                        N,N-                                        dimethylamido     2539 2     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-pyridyl                                        morpholin-1-yl     2540 2     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-pyrimidinyl                                        2-methylindazol-                                        1-yl     2541 2     (CH.sub.2).sub.2 C(O)OCH.sub.2                               2-fluorophenyl                                        N,N-dimethyl-                                        sulfamido     2542 2     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-chlorophenyl                                        pyridin-3-yl     2543 2     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-bromophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2544 2     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-pyridyl                                        pyrazol-1-yl     2545 2     (CH.sub.2).sub.2 C(O)NHCH.sub.2                               2-pyrimidinyl                                        cyclohexyl     2546 2     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-fluorophenyl                                        imidazol-1-yl     2547 2     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-chlorophenyl                                        N,N-                                        dimethylamido     2548 2     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-bromophenyl                                        morpholin-1-yl     2549 2     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-pyridyl                                        2-methylindazol-                                        1-yl     2550 2     (CH.sub.2).sub.2 NHC(O)NHCH.sub.2                               2-fluorophenyl                                        N,N-dimethyl-                                        sulfamido     2551 2     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-chlorophenyl                                        pyridin-3-yl     2552 2     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-bromophenyl                                        2-((5'-                                        trifluormethyl)                                        tetrazol-1'-                                        yl)phenyl     2553 2     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-pyridyl                                        pyrazol-1-yl     2554 2     (CH.sub.2).sub.2 S(O).sub.2 NHCH.sub.2                               2-pyrimidinyl                                        cyclohexyl     ______________________________________      *B is substituted para to Z on A.

                  TABLE 25*     ______________________________________     1 #STR46##     2 #STR47##     3 #STR48##     4 #STR49##     5 #STR50##     6 #STR51##     7 #STR52##     8 #STR53##     9 #STR54##     0 #STR55##     1 #STR56##     2 #STR57##     3 #STR58##     Ex.  D           Z      A.sup.1                                  A.sup.2                                      B     ______________________________________     2601 C(═NH)NH.sub.2                      bond   CH   CH  amino     2602 C(═NH)NH.sub.2                      bond   CH   CH  amidino     2603 C(═NH)NH.sub.2                      bond   CH   CH  guanidino     2604 C(═NH)NH.sub.2                      bond   CH   CH  2-sulfamidophenyl     2605 C(═NH)NH.sub.2                      bond   CH   CH  2-trifluoromethylphenyl     2606 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  amino     2607 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  amidino     2608 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  guanidino     2609 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  2-sulfamidophenyl     2610 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  2-trifluoromethylphenyl     2611 C(═NH)NH.sub.2                      bond   N    CH  amino     2612 C(═NH)NH.sub.2                      bond   N    CH  amidino     2613 C(═NH)NH.sub.2                      bond   N    CH  guanidino     2614 C(═NH)NH.sub.2                      bond   N    CH  2-sulfamidophenyl     2615 C(═NH)NH.sub.2                      bond   N    CH  2-trifluoromethylphenyl     2616 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  amino     2617 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  amidino     2618 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  guanidino     2619 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  2-sulfamidophenyl     2620 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  2-trifluoromethylphenyl     2621 C(═NH)NH.sub.2                      bond   N    N   amino     2622 C(═NH)NH.sub.2                      bond   N    N   amidino     2623 C(═NH)NH.sub.2                      bond   N    N   guanidino     2624 C(═NH)NH.sub.2                      bond   N    N   2-sulfamidophenyl     2625 C(═NH)NH.sub.2                      bond   N    N   2-trifluoromethylphenyl     2626 C(═NH)NH.sub.2                      CH.sub.2                             N    N   amino     2627 C(═NH)NH.sub.2                      CH.sub.2                             N    N   amidino     2628 C(═NH)NH.sub.2                      CH.sub.2                             N    N   guanidino     2629 C(═NH)NH.sub.2                      CH.sub.2                             N    N   2-sulfamidophenyl     2630 C(═NH)NH.sub.2                      CH.sub.2                             N    N   2-trifluoromethylphenyl     2631 C(═NH)NH.sub.2                      bond   CH   CH  imidazol-1-yl     2632 C(═NH)NH.sub.2                      bond   CH   CH  morpholin-1-yl     2633 C(═NH)NH.sub.2                      bond   CH   CH  2-methylimidazol-1-yl     2634 C(═NH)NH.sub.2                      bond   CH   CH  pyridin-3-yl     2635 C(═NH)NH.sub.2                      bond   CH   CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2636 C(═NH)NH.sub.2                      bond   CH   CH  pyrazol-1-yl     2637 C(═NH)NH.sub.2                      bond   CH   CH  phenyl     2638 C(═NH)NH.sub.2                      bond   CH   CH  cyclohexyl     2639 C(═NH)NH.sub.2                      bond   CH   CH  N,N-dimethylsulfamido     2640 C(═NH)NH.sub.2                      bond   CH   CH  N,N-dimethylamido     2641 C(═NH)NH.sub.2                      bond   N    CH  imidazol-1-yl     2642 C(═NH)NH.sub.2                      bond   N    CH  morpholin-1-yl     2643 C(═NH)NH.sub.2                      bond   N    CH  2-methylimidazol-1-yl     2644 C(═NH)NH.sub.2                      bond   N    CH  pyridin-3-yl     2645 C(═NH)NH.sub.2                      bond   N    CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2646 C(═NH)NH.sub.2                      bond   N    CH  pyrazol-1-yl     2647 C(═NH)NH.sub.2                      bond   N    CH  phenyl     2648 C(═NH)NH.sub.2                      bond   N    CH  cyclohexyl     2649 C(═NH)NH.sub.2                      bond   N    CH  N,N-dimethylsulfamido     2650 C(═NH)NH.sub.2                      bond   N    CH  N,N-dimethylamido     2651 C(═NH)NH.sub.2                      bond   N    N   imidazol-1-yl     2652 C(═NH)NH.sub.2                      bond   N    N   morpholin-1-yl     2653 C(═NH)NH.sub.2                      bond   N    N   2-methylimidazol-1-yl     2654 C(═NH)NH.sub.2                      bond   N    N   pyridin-3-yl     2655 C(═NH)NH.sub.2                      bond   N    N   2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2656 C(═NH)NH.sub.2                      bond   N    N   pyrazol-1-yl     2657 C(═NH)NH.sub.2                      bond   N    N   phenyl     2658 C(═NH)NH.sub.2                      bond   N    N   cyclohexyl     2659 C(═NH)NH.sub.2                      bond   N    N   N,N-dimethylsulfamido     2660 C(═NH)NH.sub.2                      bond   N    N   N,N-dimethylamido     2661 C(═NH)NH.sub.2                      bond   F    CH  imidazol-1-yl     2662 C(═NH)NH.sub.2                      bond   F    CH  morpholin-1-yl     2663 C(═NH)NH.sub.2                      bond   F    CH  2-methylimidazol-1-yl     2664 C(═NH)NH.sub.2                      bond   F    CH  pyridin-3-yl     2665 C(═NH)NH.sub.2                      bond   F    CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2666 C(═NH)NH.sub.2                      bond   F    CH  pyrazol-1-yl     2667 C(═NH)NH.sub.2                      bond   F    CH  phenyl     2668 C(═NH)NH.sub.2                      bond   F    CH  cyclohexyl     2669 C(═NH)NH.sub.2                      bond   F    CH  N,N-dimethylsulfamido     2670 C(═NH)NH.sub.2                      bond   F    CH  N,N-dimethylamido     2671 C(═NH)NH.sub.2                      bond   Cl   CH  imidazol-1-yl     2672 C(═NH)NH.sub.2                      bond   Cl   CH  morpholin-1-yl     2673 C(═NH)NH.sub.2                      bond   Cl   CH  2-methylimidazol-1-yl     2674 C(═NH)NH.sub.2                      bond   Cl   CH  pyridin-3-yl     2675 C(═NH)NH.sub.2                      bond   Cl   CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2676 C(═NH)NH.sub.2                      bond   Cl   CH  pyrazol-1-yl     2677 C(═NH)NH.sub.2                      bond   Cl   CH  phenyl     2678 C(═NH)NH.sub.2                      bond   Cl   CH  cyclohexyl     2679 C(═NH)NH.sub.2                      bond   Cl   CH  N,N-dimethylsulfamido     2680 C(═NH)NH.sub.2                      bond   Cl   CH  N,N-dimethylamido     2681 C(═NH)NH.sub.2                      bond   Br   CH  imidazol-1-yl     2682 C(═NH)NH.sub.2                      bond   Br   CH  morpholin-1-yl     2683 C(═NH)NH.sub.2                      bond   Br   CH  2-methylimidazol-1-yl     2684 C(═NH)NH.sub.2                      bond   Br   CH  pyridin-3-yl     2685 C(═NH)NH.sub.2                      bond   Br   CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2686 C(═NH)NH.sub.2                      bond   Br   CH  pyrazol-1-yl     2687 C(═NH)NH.sub.2                      bond   Br   CH  phenyl     2688 C(═NH)NH.sub.2                      bond   Br   CH  cyclohexyl     2689 C(═NH)NH.sub.2                      bond   Br   CH  N,N-dimethylsulfamido     2690 C(═NH)NH.sub.2                      bond   Br   CH  N,N-dimethylamido     2691 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  imidazol-1-yl     2692 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  morpholin-1-yl     2693 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  2-methylimidazol-1-yl     2694 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  pyridin-3-yl     2695 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2696 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  pyrazol-1-yl     2697 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  phenyl     2698 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  cyclohexyl     2699 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  N,N-dimethylsulfamido     2700 C(═NH)NH.sub.2                      CH.sub.2                             CH   CH  N,N-dimethylamido     2701 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  imidazol-1-yl     2702 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  morpholin-1-yl     2703 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  2-methylimidazol-1-yl     2704 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  pyridin-3-yl     2705 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2706 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  pyrazol-1-yl     2707 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  phenyl     2708 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  cyclohexyl     2709 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  N,N-dimethylsulfamido     2710 C(═NH)NH.sub.2                      CH.sub.2                             N    CH  N,N-dimethylamido     2711 C(═NH)NH.sub.2                      CH.sub.2                             N    N   imidazol-1-yl     2712 C(═NH)NH.sub.2                      CH.sub.2                             N    N   morpholin-1-yl     2713 C(═NH)NH.sub.2                      CH.sub.2                             N    N   2-methylimidazol-1-yl     2714 C(═NH)NH.sub.2                      CH.sub.2                             N    N   pyridin-3-yl     2715 C(═NH)NH.sub.2                      CH.sub.2                             N    N   2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2716 C(═NH)NH.sub.2                      CH.sub.2                             N    N   pyrazol-1-yl     2717 C(═NH)NH.sub.2                      CH.sub.2                             N    N   phenyl     2718 C(═NH)NH.sub.2                      CH.sub.2                             N    N   cyclohexyl     2719 C(═NH)NH.sub.2                      CH.sub.2                             N    N   N,N-dimethylsulfamido     2720 C(═NH)NH.sub.2                      CH.sub.2                             N    N   N,N-dimethylamido     2721 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  imidazol-1-yl     2722 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  morpholin-1-yl     2723 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  2-methylimidazol-1-yl     2724 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  pyridin-3-yl     2725 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2726 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  pyrazol-1-yl     2727 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  phenyl     2728 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  cyclohexyl     2729 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  N,N-dimethylsulfamido     2730 C(═NH)NH.sub.2                      CH.sub.2                             F    CH  N,N-dimethylamido     2731 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  imidazol-1-yl     2732 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  morpholin-1-yl     2733 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  2-methylimidazol-1-yl     2734 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  pyridin-3-yl     2735 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2736 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  pyrazol-1-yl     2737 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  phenyl     2738 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  cyclohexyl     2739 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  N,N-dimethylsulfamido     2740 C(═NH)NH.sub.2                      CH.sub.2                             Cl   CH  N,N-dimethylamido     2741 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  imidazol-1-yl     2742 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  morpholin-1-yl     2743 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  2-methylimidazol-1-yl     2744 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  pyridin-3-yl     2745 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  2-(5'-trifluoromethyl)                                      tetrazol-1'-yl     2746 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  pyrazol-1-yl     2747 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  phenyl     2748 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  cyclohexyl     2749 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  N,N-dimethylsulfamido     2750 C(═NH)NH.sub.2                      CH.sub.2                             Br   CH  N,N-dimethylamido     ______________________________________      *Each entry in Table 25 is intended to correspond individually to each of      formulae a-m.

UTILITY

The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms.

The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa. The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, K_(m), for substrate hydrolysis was determined at 25° C. using the method of Lineweaver and Burk. Values of K_(i) were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate K_(i) values:

    (v.sub.o -v.sub.s)/v.sub.s =I/(K.sub.i (1+S/K.sub.m))

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

K_(m) is the Michaelis constant.

Using the methodology described above, a number of compounds of the present invention were found to exhibit a K_(i) of ≦1 μm, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of the compounds of the present invention can be demonstrated in a rat vena cava thrombosis model. In this model Male Sprague-Dawley rats weighing 350-450 grams anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (110 mg/kg i.m.) are used. A carotid artery, a jugular vein and a femoral vein are cannulated for blood sampling, drug infusion and hypotonic saline injection, respectively. The abdominal vena cava is isolated and all its side-branches are ligated beneath the left renal vein. Thrombus formation is induced by rapid injection of 1 ml hypotonic saline (0.225%) into the vena cava. This is followed 15 seconds later by a 15-minute stasis of an isolated segment (about 1 cm) of the vena cava. The formed thrombus in the vena cava is removed and immediately weighed.

Test compounds or vehicle are given as continuous intravenous infusions or orally starting 1 hour before the injection of hypotonic saline. Arterial blood samples (1.5 ml) for the determination of clotting times are collected before and 1 hour after the infusion or oral dosing of test compounds or vehicle. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

The compounds of formula (I) are also considered to be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes.

Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a K_(i) of less than 5 μm, thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the disclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but no compound of the present invention, then one would conclude factor Xa was present.

DOSAGE AND FORMULATION

The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient,and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United States is:
 1. A compound of formula I: ##STR59## or stereoisomer or pharmaceutically acceptable salt form thereof, wherein; one of D and D' is selected from CN, C(═NR¹¹)NR¹² R¹³, NHC(═NR¹¹)NR¹² R¹³, NR¹² CH(═NR¹¹), C(O)NR¹² R¹³, and CH₂ NR¹² R¹³ and the other is H;R¹ is selected from H, (CH₂)_(r) OR³, halo, C₁₋₄ alkyl, (CH₂)_(r) NR⁴ R^(4'), (CH₂)_(r) CO₂ H, (CH₂)_(r) C(═O)R⁴, (CH₂)_(r) NR⁴ C(═O)R⁴, (CH₂)_(r) SO₂ R⁵, and (CH₂)_(r) NR⁴ SO₂ R⁵ ; R² and R^(2a) are on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R¹⁰ or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 R^(10a) ; R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, benzyl and phenyl; R³ and R^(3') may be taken together to form a 5 or 6 membered ring substituted with 0-2 R⁶ ; R⁴ and R^(4') are independently selected from H, OR³, C₁₋₄ alkyl, phenyl and NR³ R^(3') ; R⁵ is selected from C₁₋₄ alkyl, phenyl and NR³ R^(3') ; Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r) C(O)(CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)(CH₂)_(r), and (CH₂)_(r) S(O)_(p) (CH₂)_(r) ; A is selected from:phenyl substituted with 0-2 R⁶, pyridyl substituted with 0-2 R⁶ and piperidinyl substituted with 0-2 R⁶ ; B is selected from:Y, X--Y, NR³ R^(3'), C(O)NR³ R^(3'), and SO₂ NR³ R^(3') ; X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --C(O)NR³ --, --NR³ C(O)--, --C(O)NR³ CR³ R^(3') --, --NR³ C(O)CR³ R^(3') --, --CR³ R^(3') C(O)NR³ --, and --CR³ R^(3') NR³ C(O)--; Y is selected from:C₁₋₄ alkyl substituted with 0-2 R⁶ C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and - 6membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ; R⁶ is selected from H, OH, CF₃, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), NR³ SO₂ NR³ R^(3'), NR³ SO₂ --C₁₋₄ alkyl, SO₂ -phenyl, and NR³ SO₂ R⁸ ; R⁷ is selected from:C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ; R⁸ is selected from:C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁹ ; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁹ ; R⁹ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), NR³ SO₂ NR³ R^(3'), and NR³ SO₂ --C₁₋₄ alkyl; R¹⁰ is selected from H, OR³, halo, C₁₋₄ alkyl, CN, NO₂, NR³ R^(3'), NR³ C(O)R^(3'), NR³ C(O)OR^(3'), NR³ SO₂ -phenyl, and NR³ SO₂ --C₁₋₄ alkyl; R^(10a) if a substituent on nitrogen is selected from H and C₁₋₄ alkyl; R^(10a) if a substituent on carbon is selected from H, C₁₋₄ alkyl, NR³ R^(3'), NR³ C(O)R^(3'), NR³ C(O)OR^(3'), NR³ SO₂ -phenyl, and NR³ SO₂ --C₁₋₄ alkyl; R¹¹ is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R¹² is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl; R¹³ is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl; n is 2; m is selected from 0 and 1; p is selected from 0, 1, and 2; q is selected from 1, 2, 3, 4, and 5; and, r is selected from 0, 1, and
 2. 2. A compound according to claim 1, wherein the compound is of formula II: ##STR60## wherein; ring N contains 0-2 N atoms and is substituted with 0-2 R¹⁰ ; and,D is selected from CN, C(═NR¹¹)NR¹² R¹³, NHC(═NR¹¹)NR¹² R¹³, NR¹² CH(═NR¹¹), C(O)NR¹² R¹³, and CH₂ NR¹² R¹³.
 3. A compound according to claim 2, wherein:D is C(═NH)NH₂ or CH₂ NR¹² R¹³ ; R¹ is selected from H, (CH₂)_(r) OR³, halo, (CH₂)_(r) NR⁴ R^(4'), (CH₂)_(r) CO₂ H, (CH₂)_(r) C(═O)R⁴, (CH₂)_(r) NR⁴ C(═O)R⁴, (CH₂)_(r) SO₂ R⁵, and (CH₂)_(r) NHSO₂ R⁵ ; R⁴ and R^(4') are independently selected from H, OR³, C₁₋₄ alkyl, and NR³ R^(3') ; R⁵ is selected from C₁₋₄ alkyl and NR³ R^(3') ; Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r) C(O)(CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)(CH₂)_(r), and (CH₂)_(r) S(O)_(p) (CH₂)_(r) ; and, X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --C(O)NR³ --, and --NR³ C(O)--.
 4. A compound according to claim 3, wherein:Z is selected from a bond, C₁₋₄ alkylene, C(O)(CH₂)_(r), C(O)NR³ (CH₂)_(r), S(O)₂, and S(O)₂ CH₂ ; and, X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3'), --CR³ R^(3') C(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, and --C(O)NR³ --.
 5. A compound according to claim 4, wherein the compound is selected from:1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;
 1. 2,4,5-tetrahydro-2-(thiopen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one; and, 1,2,4,5-tetrahydro-2-(thiophen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one.
 6. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 7. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
 8. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 9. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
 10. A compound according to claim 4, wherein:A is phenyl substituted with 0-1 R⁶.
 11. A compound according to claim 4, wherein:A is pyridyl substituted with 0-1 R⁶.
 12. A compound according to claim 4, wherein:A is piperidinyl substituted with 0-1 R⁶.
 13. A compound according to claim 1, wherein:D is C(═NH)NH₂ or CH₂ NR¹² R¹³ ; R¹ is selected from H, (CH₂)_(r) OR³, halo, (CH₂)_(r) NR⁴ R^(4'), (CH₂)_(r) CO₂ H, (CH₂)_(r) C(═O)R⁴, (CH₂)_(r) NR⁴ C(═O)R⁴, (CH₂)_(r) SO₂ R⁵, and (CH₂)_(r) NHSO₂ R⁵ ; R⁴ and R^(4') are independently selected from H, OR³, C₁₋₄ alkyl, and NR³ R^(3') ; R⁵ is selected from C₁₋₄ alkyl and NR³ R^(3') ; Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r) C(O)(CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)₂ NR³ C(O)(CH₂)_(r), and (CH₂)_(r) S(O)_(p) (CH₂)_(r) ; and, X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --C(O)NR³ --, and --NR³ C(O)--.
 14. A compound according to claim 13, wherein:Z is selected from a bond, C₁₋₄ alkylene, C(O)(CH₂)_(r), C(O)NR³ (CH₂)_(r), S(O)₂, and S(O)₂ CH₂ ; and, X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O)--, --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, and --C(O)NR³ --.
 15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
 16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
 17. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt thereof.
 18. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
 19. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
 20. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt thereof. 